Antipicornaviral compounds and compositions, their uses, and materials for their synthesis

ABSTRACT

Compounds of the formula:  
                 
 
     where the formula variables are as defined in the disclosure, advantageously inhibit or block the biological activity of the picornaviral 3C protease. These compounds, as well as pharmaceutical compositions containing these compounds, are useful for treating patients or hosts infected with one or more picornaviruses, such as RVP. Intermediates and synthetic methods for preparing such compounds are also described.

[0001] This application is a divisional of U.S. patent application Ser.No. 09/834,783, filed Apr. 12, 2001, which claims the benefit of U.S.Provisional Patent Application No. 60/197,796, filed Apr. 14, 2000 andU.S. Provisional Patent Application No. 60/198,497, filed Apr. 18, 2000,the disclosures of each of which are incorporated by reference herein.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The invention relates to pyrrole-containing peptidomimeticcompounds that inhibit the enzymatic activity of picornaviral 3Cproteases, especially rhinovirus 3C proteases (RVPs), and that retardviral growth in cell culture. The invention also relates to the use ofthese compounds in pharmaceutical compositions, methods of treatment ofrhinoviral infections using these compounds and compositions, andprocesses for the synthesis of these compounds and compounds useful inthe syntheses thereof.

[0004] 2. Related Background Art

[0005] The picornaviruses are a family of tiny non-envelopedpositive-stranded RNA-containing viruses that infect humans and otheranimals. These viruses include the human rhinoviruses, humanpolioviruses, human coxsackieviruses, human echoviruses, human andbovine enteroviruses, encephalomyocarditis viruses, meningitis virus,foot and mouth viruses, hepatitis A virus, and others. The humanrhinoviruses are a major cause of the common cold. To date, there are noeffective therapies on the market that cure the common cold, onlytreatments that relieve the symptoms.

[0006] Picornaviral infections may be treated by inhibiting theproteolytic picornaviral 3C enzymes. These enzymes are required for thenatural maturation of the picornaviruses. They are responsible for theautocatalytic cleavage of the genomic, large polyprotein into theessential viral proteins. Members of the 3C protease family are cysteineproteases, where the sulfhydryl group most often cleaves theglutamine-glycine amide bond. Inhibition of 3C proteases is believed toblock proteolytic cleavage of the viral polyprotein, which in turn canretard the maturation and replication of the viruses by interfering withviral particle production. Therefore, inhibiting the processing of thiscysteine protease with selective small molecules that are specificallyrecognized should represent an important and useful approach to treatand cure viral infections of this nature and, in particular, the commoncold.

[0007] Some small-molecule inhibitors of the enzymatic activity ofpicornaviral 3C proteases (i.e., antipicornaviral compounds) have beenrecently discovered. See, for example: U.S. Pat. No. 5,856,530; U.S.Pat. No. 5,962,487; U.S. Pat. No. 6,020,371; and U.S. patent applicationSer. No. 09/301,977, filed Apr. 29, 1999, by Dragovich et al. See also:Dragovich et al., “Structure-Based Design, Synthesis, and BiologicalEvaluation of Irreversible Human Rhinovirus 3C Protease Inhibitors . . .,” J. Med. Chem. (1999), Vol. 42, No. 7, 1203-1212, 1213-1224; andDragovich et al., “Solid-phase Synthesis of Irreversible HumanRhinovirus 3C Protease Inhibitors . . . ,” Bioorg. & Med. Chem. (1999),Vol. 7, 589-598. There remains a desire, to discover small-moleculecompounds that are especially potent antipicornaviral agents.

[0008] Inhibitors of other related cysteine proteases such as cathepsinshave been described in, e.g., U.S. Pat. No. 5,374,623; U.S. Pat. No.5,498,616; and WIPO International Publication Nos. WO 94/04172, WO95/15749, WO 97/19231, and WO 97/49668. There yet remains a need forinhibitors targeting the picornaviral 3C cysteine protease withdesirable pharmaceutical properties, such as high specificity, goodtherapeutic index or low toxicity.

SUMMARY OF THE INVENTION

[0009] This invention relates to compounds useful for inhibiting theactivity of picornaviral 3C proteases having the general Formula I:

[0010] wherein:

[0011] R^(a) is an alkylcarbonylalkyl, cycloalkylcarbonylalkyl,arylcarbonylalkyl, heteroarylcarbonylalkyl, alkylcarbonylaminoalkyl,cycloalkylcarbonylaminoalkyl, heterocycloalkylcarbonylaminoalkyl,arylcarbonylaminoalkyl, heteroarylcarbonylaminoalkyl,alkylaminocarbonylalkyl, cycloalkylaminocarbonylalkyl,heterocycloalkylaminocarbonylalkyl, arylaminocarbonylalkyl,heteroarylaminocarbonylalkyl group, where each alkyl, cycloalkyl,heterocycloalkyl, aryl and heteroaryl moiety thereof is unsubstituted orsubstituted with one or more suitable substituents;

[0012] R^(b) is H or an alkyl group, unsubstituted or substituted withone or more suitable substituents;

[0013] R^(d) is H, halo, hydroxyl, or an alkyl, alkoxy or alkylthiogroup, where the alkyl, alkoxy or alkylthio group is unsubstituted orsubstituted with one or more suitable substituents;

[0014] R^(c) is a moiety having the formula:

[0015] R^(e) and R^(f) are each independently H or a lower alkyl group;

[0016] m is 0 or 1, provided that when m is 1, R^(a) is not anamino-substituted alkylcarbonylalkyl or amino-substitutedalkylcarbonylaminoalkyl group, and when m is 0, R^(a) is selected froman alkylaminocarbonylalkyl, cycloalkylaminocarbonylalkyl,heterocycloalkylaminocarbonylalkyl, arylaminocarbonylalkyl,heteroarylaminocarbonylalkyl and heteroarylcarbonylaminoalkyl group,provided that R^(a) is not substituted indolecarbonylaminoalkyl;

[0017] p is an integer of from 0 to 5;

[0018] A₁ is CH or N;

[0019] when p is 1, 2, 3, 4, or 5, A₂ is C(R^(g)(R^(b)), N(R^(i)), S,S(O), S(O)₂, or O, and when p is 0, A₂ is C(R^(g))(R^(h))(R^(i)),N(R^(g))(R^(i)), S(R^(g)), S(O)(R^(g)), S(O)₂(R^(g)), or O(R^(g)), whereeach R^(g), R^(h) and R^(i) is independently H or a lower alkyl group;

[0020] each A₃ present is each independently C(R^(g))(R^(h)), N(R^(i)),S, S(O), S(O)₂, or O, where each R^(g), R^(h) and R^(i) is independentlyH or a lower alkyl group;

[0021] when p is 1, 2, 3, 4, or 5, A₄ is N(R^(j)), C(R^(g))(R^(h)), orO, and when p is 0 (i.e., A₃ is not present), A₄ is N(R^(j))(R^(k)),C(R^(g))(R^(h))(R^(i)), and O(R^(k)), where each R^(g), R^(h) and R^(i)is independently H or a lower alkyl group, each R^(j) is H, an alkyl,aryl, or acyl group, and each R^(k) is H or an alkyl or aryl group;

[0022] provided that no more than two heteroatoms occur consecutively inthe above-depicted ring formed by A₁, (A₂)_(m), (A₃)_(p), A₄, and C═O,where each dotted line in the ring depicts a single bond when A₂ ispresent (i.e., m=1) and a hydrogen atom when A₂ is absent (i.e., n=0);and

[0023] Z and Z¹ are each independently H, F, an alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl group, where the alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl group is unsubstituted orsubstituted with one or more suitable substituents, —C(O)R^(l),—CO₂R^(l), —CN, —C(O)NR^(l)R^(m), —C(O)NR^(l)OR^(m), —C(S)R^(l),—C(S)OR^(l)—C(S)NR^(l)R^(m), —C(═NR^(l))R^(m), —C(═NR^(l))OR^(m), —NO₂,—SOR^(m), —SO₂R^(l), —SO₂NR^(l)R^(m), —SO₂(NR^(l))(OR^(m)), —SONR^(l),—SO₃R^(l), —PO(OR^(l))₂, —PO(OR^(l))(OR^(m)), —PO(NR^(l)R^(m))(OR^(n)),—PO(NR^(l)R^(m))(NR^(n)R^(o)), —C(O)NR^(l)NR^(m)R^(n),—C(S)NR^(l)NR^(m)R^(n), where R^(l), R^(m), R^(n) and R^(o) are eachindependently H or an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl orthioacyl group, where the alkyl, cycloalkyl, aryl, heterocycloalkyl,acyl or thioacyl group is unsubstituted or substituted with one or moresuitable substituents, or where any two of the R^(l), R^(m), R^(n) andR^(o), taken together with the atoms to which they are bonded, form aheterocycloalkyl group, which may be optionally substituted,

[0024] or Z and R^(d), together with the atoms to which they are bonded,form a cycloalkyl or heterocycloalkyl group, where Z and R^(d) are asdefined above except for moieties that cannot form the cycloalkyl orheterocycloalkyl group,

[0025] or Z and Z¹, together with the atoms to which they are bonded,form a cycloalkyl or heterocycloalkyl group, where Z and Z¹ are asdefined above (except for moieties that cannot form the cycloalkyl orheterocycloalkyl group);

[0026] or a prodrug, pharmaceutically acceptable salt, pharmaceuticallyactive metabolite, or pharmaceutically acceptable solvate of saidcompound.

[0027] In another embodiment of the compounds of the above Formula I,

[0028] A₁ is CH or N;

[0029] A₂ is C(R^(g))(R^(h)), N(R^(i)), S, S(O), S(O)₂, or O, where eachR^(g), R^(h) and R^(i) is independently H or a lower alkyl group;

[0030] each A₃ present is independently C(R^(g))(R^(h)), N(R^(i)), S,S(O), S(O)₂, or O, where each R^(g), R^(h) and R^(i) is independently Hor a lower alkyl group;

[0031] when p is 1, 2, 3, 4, or 5, A₄ is N(R^(i)), C(R^(g))(R^(h)), orO, and when p is 0, A₄ is N(R^(j))(R^(k)), C(R^(g))(R^(h))(R^(i)), andO(R^(k)), where each R^(g), R^(h) and R^(i) is independently H or alower alkyl group, each R^(j) is H, an alkyl, aryl, or acyl group, andeach R^(k) is H or an alkyl or aryl group;

[0032] provided that no more than two heteroatoms occur consecutively inthe above-depicted ring formed by A₁, (A₂)_(m), (A₃)_(p), A₄, and C═O,where each dotted line in the ring depicts a single bond when A₂ ispresent and a hydrogen atom when A₂ is absent; and

[0033] Z and Z¹ are each independently H, F, an alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl group, where the alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl group is unsubstituted orsubstituted with one or more suitable substituents, —C(O)R^(l),—CO₂R^(l), —CN, —C(O)NR^(l)R^(m), —C(O)NR^(l)OR^(m), —C(S)R^(l),—C(S)NR^(l)R^(m), —NO₂, —SOR^(m), —SO₂R^(l), —SO₂NR^(l)R^(m),—SO₂(NR^(l))(OR^(m)), —SONR^(l), —SO₃R^(l), —PO(OR^(l))₂,—PO(OR^(l))(OR^(m)), —PO(NR^(l)R^(m))(OR^(n)),—PO(NR^(l)R^(m))(NR^(n)R^(o)), —C(O)NR^(l)NR^(m)R^(n),—C(S)NR^(l)NR^(m)R^(n), where R^(l), R^(m), R^(n) and R^(o) are eachindependently H, an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl orthioacyl group, where the alkyl, cycloalkyl, aaryl, heterocycloalkyl,acyl or thioacyl group is unsubstituted or substituted with one or moresuitable substituents, or where any two of the R^(l), R^(m), R^(n) andR^(o), taken together with the atoms to which they are bonded, form aheterocycloalkyl group, which is unsubstituted or substituted with oneor more suitable substituents, or Z and Z¹, together with the atoms towhich they are bonded, form a cycloalkyl or heterocycloalkyl group,where Z and Z¹ are as defined above.

[0034] One embodiment of this invention relates to compounds useful forinhibiting the activity of picornaviral 3C proteases having thefollowing general Formula II:

[0035] wherein R^(a′) is an alkyl, cycloalkyl, aryl or heteroaryl group,where the alkyl, cycloalkyl, aryl or heteroaryl group is unsubstitutedor substituted with one or more suitable substituents, n is 1, 2 or 3, mis 1, R^(x) and R^(y) are each independently selected from H and analkyl group, unsubstituted or substituted with one or more suitablesubstituents, and R^(b), R^(c), R^(d), Z and Z¹ are as defined above,provided that R^(a′) is not an amino-substituted alkyl group.

[0036] Another embodiment of this invention relates to compounds usefulfor inhibiting the activity of picornaviral 3C proteases having thefollowing general Formula III:

[0037] wherein R^(a′) is an alkyl, cycloalkyl, aryl or heteroaryl group,where the alkyl, cycloalkyl, aryl or heteroaryl group is unsubstitutedor substituted with one or more suitable substituents, n is 1, 2 or 3, mis 1, R^(x) and R^(y) are each independently selected from H and analkyl group, unsubstituted or substituted with one or more suitablesubstituents, and R^(b), R^(c), R^(d), Z and Z¹ are as defined above,provided that R^(a′) is not an amino-substituted alkyl group.

[0038] This invention also relates to compounds useful for inhibitingthe activity of picornaviral 3C proteases having the following generalFormula IV:

[0039] wherein R^(a′) is an alkyl, aryl, cycloalkyl, heterocycloalkyl orheteroaryl group, where the alkyl, aryl, cycloalkyl, heterocycloalkyland heteroaryl group is unsubstituted or substituted with one or moresuitable substituents, n is 1, 2 or 3, R^(x) and R^(y) are eachindependently selected from H and an alkyl group, unsubstituted orsubstituted with one or more suitable substituents, and R^(b), R^(c),R^(d), Z and Z¹ are as defined above.

[0040] This invention relates to compounds useful for inhibiting theactivity of picornaviral 3C proteases having the general Formula V:

[0041] wherein:

[0042] W is CH or N;

[0043] R¹ is H, halo or an alkoxy, alkyl, aryl, cycloalkyl,heterocycloalkyl or heteroaryl group, where the alkoxy, alkyl, aryl,cycloalkyl, heterocycloalkyl and heteroaryl group is unsubstituted orsubstituted with one or more suitable substituents;

[0044] R² and R³ are each independently H, halo or an alkoxy or loweralkyl group, where the alkoxy or lower alkyl group is unsubstituted orsubstituted with a suitable substituent;

[0045] or R¹ together with R² form a cycloalkyl, heterocycloalkyl, arylor heteroaryl ring, where the cycloalkyl, heterocycloalkyl, aryl orheteroaryl ring is unsubstituted or substituted with a suitablesubstituent;

[0046] R⁴ and R⁶ are each independently H or a lower alkyl group,unsubstituted or substituted with a suitable substituent;

[0047] R⁵ is H or an alkyl group, unsubstituted or substituted with asuitable substituent;

[0048] R⁷ is a moiety having the formula:

[0049] wherein:

[0050] R⁸ and R⁹ are each independently H or a lower alkyl group;

[0051] m is 0 or 1, provided that when W is N, m is 0 and R¹ togetherwith R² form an aryl ring, the aryl ring is unsubstituted (e.g., R¹together with R² and the pyrrole to which they are bound do not form asubstituted indole);

[0052] p is an integer of from 0 to 5;

[0053] A is CH or N;

[0054] when p is 1, 2, 3, 4, or 5, A₂ is C(R¹⁰)(R¹¹), N(R¹²), S, S(O),S(O)₂, or O, and when p is 0, A₂ is C(R¹⁰)(R¹¹)(R¹²), N(R¹⁰)(R¹²),S(R¹⁰), S(O)(R¹⁰), S(O)₂(R¹⁰), or O(R¹⁰) where each R¹⁰, R¹¹ and R¹² isindependently H or a lower alkyl group;

[0055] each A₃ present is independently C(R¹⁰)(R¹¹), N(R¹²), S, S(O),S(O)₂, or O, where each R¹⁰, R¹¹ and R¹² is independently H or a loweralkyl group;

[0056] when p is 1, 2, 3, 4, or 5, A₄ is N(R¹³), C(R¹⁰)(R¹¹), or O, andwhen p is 0, A₄ is N(R¹³)(R¹⁴), C(R¹⁰)(R¹¹)(R¹²), and O(R¹⁴), where eachR¹⁰, R¹¹ and R¹² is independently H or a lower alkyl group, each R¹³ isH or an alkyl, aryl, or acyl group, and each R¹⁴ is H or an alkyl oraryl group;

[0057] provided that no more than two heteroatoms occur consecutively inthe above-depicted ring formed by A₁, (A₂)_(m), (A₃)_(p), A₄, and C═O,where each dotted line in the ring depicts a single bond when A₂ ispresent and a hydrogen atom when A₂ is absent; and

[0058] Z and Z¹ are each independently H, F, an alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl group, where the alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl group is unsubstituted orsubstituted with one or more suitable substituents, —C(O)R¹⁵, —CO₂R¹⁵,—CN, —C(O)NR¹⁵R¹⁶, —C(O)NR¹⁵OR¹⁶, —C(S)R¹⁵, —C(S)OR¹⁵, —C(S)NR¹⁵R¹⁶,—C(═NR¹⁵)R¹⁶, —C(═NR¹⁵)OR¹⁶, —NO₂, —SOR¹⁶, —SO₂R¹⁵, —SO₂NR¹⁵R¹⁶,—SO₂(NR¹⁵)(OR¹⁶), —SONR¹⁵, —SO₃R¹⁵, —PO(OR¹⁵)₂, —PO(OR¹⁵)(OR¹⁶),—PO(NR¹⁵R¹⁶)(OR¹⁷), —PO(NR¹⁵R¹⁶)(NR¹⁷R¹⁸), —C(O)NR¹⁵NR¹⁶R¹⁷,—C(S)NR¹⁵NR¹⁶R¹⁷, where R¹⁵, R¹⁶, R¹⁷ and R¹⁸ are each independently Hor an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacyl group,where the alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacylgroup is unsubstituted or substituted with one or more suitablesubstituents, or where any two of the R¹⁵, R¹⁶, R¹⁷ and R¹⁸, takentogether with the atoms to which they are bonded, form aheterocycloalkyl group, which is unsubstituted or substituted with oneor more suitable substituents,

[0059] or Z and Z¹, together with the atoms to which they are bonded,form a cycloalkyl or heterocycloalkyl group, where Z and Z¹ are asdefined above (except for moieties that cannot form the cycloalkyl orheterocycloalkyl group).

[0060] In another embodiment of the compounds of Formula V,

[0061] A₁ is CH or N;

[0062] A₂ is C(R¹⁰)(R¹¹), N(R¹²), S, S(O), S(O)₂, or O, where each R¹⁰,R¹¹ and R¹² is independently H or a lower alkyl group;

[0063] each A₃ present is independently C(R¹⁰)(R¹¹), N(R¹²), S, S(O),S(O)₂, or O, where each R¹⁰, R¹¹ and R¹² is independently H or a loweralkyl group;

[0064] when p is 1, 2, 3, 4, or 5, A₄ is N(R¹³), C(R¹⁰)(R¹¹), or O, andwhen p is 0, A₄ is N(R¹³)(R¹⁴), C(R¹⁰)(R¹¹)(R¹²), and O(R¹⁴), where eachR¹⁰, R¹¹ and R¹² is independently H or a lower alkyl group, each R¹³ isH or an alkyl, aryl, or acyl group, and each R¹⁴ is H or an alkyl oraryl group;

[0065] provided that no more than two heteroatoms occur consecutively inthe above-depicted ring formed by A₁, (A₂)_(m), (A₃)_(p), A₄, and C═O,where each dotted line in the ring depicts a single bond when A₂ ispresent and a hydrogen atom when A₂ is absent; and

[0066] Z and Z¹ are each independently H, F, an alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl group, where the alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl group is unsubstituted orsubstituted with one or more suitable substituents, —C(O)R¹⁵, —CO₂R¹⁵,—CN, —C(O)NR¹⁵R¹⁶, —C(O)NR¹⁵OR¹⁶, —C(S)R¹⁵, —C(S)NR¹⁵R¹⁶, —NO₂, —SOR¹⁶,—SO₂R¹⁵, —SO₂NR¹⁵R¹⁶, —SO₂(NR¹⁵)(OR¹⁶), —SONR¹⁵, —SO₃R¹⁵, —PO(OR¹⁵)₂,—PO(OR¹⁵)(OR¹⁶), —PO(NR¹⁵R¹⁶)(OR¹⁷), —PO(NR¹⁵R¹⁶)(NR¹⁷R¹⁸),—C(O)NR¹⁵NR¹⁶R¹⁷, —C(S)NR¹⁵NR¹⁶R¹⁷, where R¹⁵, R¹⁶, R¹⁷ and R¹⁸ are eachindependently H or an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl orthioacyl group, where the alkyl, cycloalkyl, aryl, heterocycloalkyl,acyl or thioacyl group is unsubstituted or substituted with one or moresuitable substituents, or where any two of the R¹⁵, R¹⁶, R¹⁷ and R¹⁸,taken together with the atoms to which they are bonded, form aheterocycloalkyl group, which is unsubstituted or substituted with oneor more suitable substituents, or Z and Z¹, together with the atoms towhich they are bonded, form a cycloalkyl or heterocycloalkyl group,where Z and Z¹ are as defined above.

[0067] In the compounds of the above-described Formulas I-V, R^(c) andR⁷ are defined to provide structures where m is 1 and p is 1-5 (i.e.,both A₂ and A₃ are present), m is 0 and p is 0 (i.e, both A₂ and A₃ areabsent), m is 0 and p is 1-5 (i.e, A₂ is absent and A₃ is present) and mis 1 and p is 0 (i.e, A₂ is present and A₃ is absent). Accordingly, oneof ordinary skill in the are will recognize that when both A₂ and A₃ arepresent (m is 1 and p is 1-5), the dotted line between A₁ and A₂represents a bond and the dotted line between A₂ and A₃ represents abond. Wwhen both A₂ and A₃ are absent (m is 0 and p is 0) A₂, A₃ and thedotted line between these substituents are not present and the remainingdotted line in the structure between A₁ and A₂ represents a hydrogen(e.g., A₁ is CH₂ or NH). In embodiments of this invention when A₂ isabsent and A₃ is present (m is 0 and p is 1-5), the dotted line betweenA₁ and A₂ represents a hydrogen and the dotted line between A₂ and A₃represents a hydrogen (e.g., A₁ is CH₂ or NH and A₃ is CH(R^(g))(R^(h)),NH(R^(i)), SH, S(O)H, S(O)₂H, or OH or CH(R¹⁰)(R¹¹), NH(R¹²), SH, S(O)H,S(O)₂H, or OH); and when A₂ is present and A₃ is absent (m is 1 and p is0), the dotted line between A₁ and A₂ represents a bond and A₂ isC(R^(g))(R^(h))(R^(i)), N(R^(g))(R^(i)), S(R^(g)), S(O)(R^(g)),S(O)₂(R^(g)), or O(R^(g)) or A₂ is C(R¹⁰)(R¹¹)(R¹²), N(R¹⁰)(R¹²),S(R¹⁰), S(O)(R¹⁰), S(O)₂(R¹⁰), or O(R¹⁰) or the dotted line between A₂and A₃ represents a hydrogen and A₂ is CH(R^(g))(R^(h)), NH(R^(i)), SH,S(O)H, S(O)₂H, or OH or A₂ is CH(R¹⁰)(R¹¹), NH(R¹²), SH, S(O)H, S(O)₂H,or OH. In preferred embodiments of the compounds of Formula I-V of thisinvention, m is 1 and p is 1 or 2 or m is 0 and p is 0 or m is 1 and pis 0. More preferably, when m is 1 and p is 1 or 2, A₂ and A₃ are bothC(R^(g))(R^(h)) or C(R¹⁰)(R¹¹), respectively. More preferably, m is 1and p is 1.

[0068] In addition to compounds of the Formulas I-V, antipicornaviralagents of the invention include prodrugs, pharmaceutically activemetabolites, and pharmaceutically acceptable salts and solvates of suchcompounds.

DETAILED DESCRIPTION OF INVENTION

[0069] In accordance with a convention used in the art,

[0070] is used in structural formulas herein to depict the bond that isthe point of attachment of the moiety or substituent to the core orbackbone structure.

[0071] As used herein, the term “alkyl” represents a straight- orbranched-chain saturated or unsaturated hydrocarbon, containing 1 to 10carbon atoms which may be unsubstituted or substituted by one or more ofthe substituents described below. A C₁-C₆ alkyl represents an alkylsubstituent containing 1 to 6 carbon atoms. Exemplary alkyl substituentsinclude, but are not limited to methyl (Me), ethyl (Et), propyl,isopropyl, butyl, isobutyl, t-butyl, ethenyl, propenyl, butenyl,pentenyl, ethynyl, butynyl, propynyl (propargyl, isopropynyl), pentynyl,hexynyl and the like. The term “lower alkyl” refers to an alkyl groupcontaining from 1 to 4 carbon atoms.

[0072] “Cycloalkyl” represents a group comprising a non-aromaticmonocyclic, bicyclic, or tricyclic hydrocarbon containing from 3 to 14carbon atoms which may be unsubstituted or substituted by one or more ofthe substituents described below and may be saturated or unsaturated.Exemplary cycloalkyls include monocyclic rings having from 3-7,preferably 3-6, carbon atoms, such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and the like, that may be fullysaturated or partially unsaturated. Illustrative examples of cycloalkylgroups include the following:

[0073] “Heterocycloalkyl” represents a group comprising a non-aromatic,monovalent monocyclic, bicyclic, or tricyclic radical, which issaturated or partially unsaturated, containing 3 to 18 ring atoms, whichincludes 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur,and which may be unsubstituted or substituted by one or more of thesubstituents described below. Illustrative examples of heterocycloalkylgroups include, but are not limited to, azetidinyl, pyrrolidyl,piperidyl, piperazinyl, morpholinyl, tetrahydro-2H-1,4-thiazinyl,tetrahydrofuryl, dihydrofuryl, tetrahydropyranyl, dihydropyranyl,1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-oxathiolanyl,1,3-oxathianyl, 1,3-dithianyl, azabicyclo[3.2.1]octyl,azabicyclo[3.3.1]nonyl, azabicyclo[4.3.0]nonyl, oxabicyclo[2.2.1]heptyl,1,5,9-triazacyclododecyl, and the like. Illustrative examples ofheterocycloalkyl groups include the following moieties:

[0074] wherein R is H, alkyl or hydroxyl.

[0075] “Aryl” represents a group comprising an aromatic, monovalentmonocyclic, bicyclic, or tricyclic radical containing from 6 to 18carbon ring atoms, which may be unsubstituted or substituted by one ormore of the substituents described below, and to which may be fused oneor more cycloalkyl groups, heterocycloalkyl groups or heteroaryl groups,which themselves may be unsubstituted or substituted by one or moresuitable substituents. Illustrative examples of aryl groups include thefollowing moieties:

[0076] “Heteroaryl” represents a group comprising an aromatic monovalentmonocyclic, bicyclic, or tricyclic radical, containing 5 to 18 ringatoms, including 1 to 5 heteroatoms selected from nitrogen, oxygen andsulfur, which may be unsubstituted or substituted by one or more of thesubstituents described below. As used herein, the term “heteroaryl” isalso intended to encompass the N-oxide derivative (or N-oxidederivatives, if the heteroaryl group contains more than one nitrogensuch that more than one N-oxide derivative may be formed) of thenitrogen-containing heteroaryl groups described herein. Illustrativeexamples of heteroaryl groups include, but are not limited to, thienyl,pyrrolyl, imidazolyl, pyrazolyl, furyl, isothiazolyl, furazanyl,isoxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,triazinyl, benzo[b]thienyl, naphtho[2,3-b]thianthrenyl, isobenzofuranyl,chromenyl, xanthenyl, phenoxathienyl, indolizinyl, isoindolyl, indolyl,indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl,quinoxyalinyl, quinzolinyl, benzothiazolyl, benzimidazolyl,tetrahydroquinolinyl, cinnolinyl, pteridinyl, carbazolyl,beta-carbolinyl, phenanthridinyl, acridinyl, perimidinyl,phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, andphenoxazinyl. Illustrative examples of N-oxide derivatives of heteroarylgroups include, but are not limited to, pyridyl N-oxide, pyrazinylN-oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, triazinyl N-oxide,isoquinolyl N-oxide, and quinolyl N-oxide. Further examples ofheteroaryl groups include the following moieties:

[0077] wherein R is H, alkyl or hydroxyl.

[0078] The term “suitable substituent” represents a substituent that isoptionally present on any of the above alkyl, aryl, cycloalkyl,heterocycloalkyl or heteroaryl groups, described herein, and is selectedfrom alkyl (except for alkyl) haloalkyl, haloaryl, halocycloalkyl,haloheterocycloalkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl,nitro, amino, hydroxamino, cyano, halo, hydroxyl, alkoxy, alkylenedioxy,aryloxy, cycloalkoxy, heterocycloalkoxy, heteroaryloxy, alkylcarbonyl,alkyloxycarbonyl, alkylcarbonyloxy, arylcarbonyl, arylcarbonyloxy,aryloxycarbonyl, cycloalkylcarbonyl, cycloalkylcarbonyloxy,cycloalkyoxycarbonyl, heteroarylcarbonyl, heteroarylcarbonyloxy,heteroaryloxycarbonyl, heterocycloalkylcarbonyl,heterocycloalkylcarbonyloxy, heterocycloalkyoxycarbonyl, carboxyl,carbamoyl, formyl, keto (oxo), thioketo, sulfo, alkylamino,cycloalkylamino, arylamino, heterocycloalkylamino, heteroarylamino,dialkylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl,arylaminocarbonyl, heterocycloalkylaminocarbonyl,heteroarylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl,cycloalkylaminothiocarbonyl, arylaminothiocarbonyl,heterocycloalkylaminothiocarbonyl, heteroarylaminothiocarbonyl,dialkylaminothiocarbonyl, alkylsulfonyl, arylsulfonyl, alkylsulfenyl,arylsulfenyl, alkylcarbonylamino, cycloalkylcarbonylamino,arylcarbonylamino, heterocycloalkylcarbonylamino,heteroarylcarbonylamino, alkylthiocarbonylamino,cycloalkylthiocarbonylamino, arylthiocarbonylamino,heterocycloalkylthiocarbonylamino, heteroarylthiocarbonylamino,alkylsulfonyloxy, arylsulfonyloxy, alkylsulfonylamino,arylsulfonylamino, mercapto, alkylthio, arylthio, and heteroarylthiogroups, where any of the alkyl, alkylene, aryl, cycloalkyl,heterocycloalkyl, heteroaryl moieties present in the above substituentsmay be further substituted with one or more substituents selected fromnitro, amino, cyano, halo, haloalkyl, haloaryl, hydroxyl, keto,hydroxamino, alkylamino, dialkylamino, mercapto, and unsubstitutedalkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkoxy, aryloxy,alkylthio or arylthio groups and where any of the aryl or heteroarylmoieties may be substituted with alkylenedioxy. Preferred “suitablesubstituents” include alkyl, aryl, cycloalkyl, heterocycloalkyl,heteroaryl, halo, hydroxyl, alkoxy, alkylenedioxy, aryloxy, cycloalkoxy,heteroaryloxy, and carboxyl. The alkyl, alkylene, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl moieties of any of the abovesubstituents may be optionally substituted by one or more of alkyl(except for alkyl), halo, haloalkyl, aryl or heteroaryl, where the arylor heteroaryl is unsubstituted or substituted with one or moresubsituents, (e.g., haloaryl), independently selected from alkyl,haloalkyl, alkylenedioxy, nitro, amino, hydroxamino, alkylamino,dialkylamino, halo, hydroxyl, alkoxy, haloalkoxy, aryloxy, mercapto,alkylthio or arylthio groups.

[0079] The terms “halogen” and “halo” represent chloro, fluoro, bromo oriodo substituents. “Heterocycle” is intended to mean a heteroaryl orheterocycloalkyl group. “Acyl” is intended to mean a —C(O)—R radical,wherein R is an alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroarylgroup. “Acyloxy” is intended to mean an —OC(O)—R radical, wherein R isan alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl group.“Thioacyl” is intended to mean a —C(S)—R radical, wherein R is an alkyl,cycloalkyl, aryl, heterocycloalkyl or heteroaryl group. “Sulfonyl” isintended to mean an —SO₂— biradical. “Sulfenyl” is intended to mean an—SO— biradical. “Sulfo” is intended to mean an —SO₂H radical. Sulfoxideis intended to mean a —SO₃ ⁻ radical “Hydroxy” is intended to mean theradical —OH. “Amine” or “amino” is intended to mean the radical —NH₂.“Alkylamino” is intended to mean the radical —NHR_(a), wherein R_(a) isan alkyl group. “Dialkylamino” is intended to mean the radical—NR_(a)R_(b), wherein R_(a) and R_(b) are each independently an alkylgroup, and is intended to include heterocycloalkyl groups, wherein R_(a)and R_(b), taken together, form a heterocyclic ring that includes theamine nitrogen. “Hydroxamino” is intended to mean the radical —N—OH.“Alkoxy” is intended to mean the radical —OR_(a), wherein R_(a) is analkyl group. Exemplary alkoxy groups include methoxy, ethoxy, propoxy,and the like. “Lower alkoxy” groups have alkyl moieties having from 1 to4 carbons. “Alkylenedioxy” is intended to mean the divalent radical—OR_(a)O— which is bonded to adjacent atoms on an aryl or heteroarylmoiety (e.g., adjacent atoms on a phenyl or naphthyl ring), whereinR_(a) is a lower alkyl group. “Alkoxycarbonyl” is intended to mean theradical —C(O)OR_(a), wherein R_(a) is an alkyl group. “Alkylsulfonyl” isintended to mean the radical —SO₂R_(a), wherein R_(a) is an alkyl group.“Alkylaminocarbonyl” is intended to mean the radical —C(O)NHR_(a),wherein R_(a) is an alkyl group. “Dialkylaminocarbonyl” is intended tomean the radical —C(O)NR_(a)R_(b), wherein R_(a) and R_(b) are eachindependently an alkyl group. “Mercapto” is intended to mean the radical—SH. “Alkylthio” is intended to mean the radical —SR_(a), wherein R_(a)is an alkyl group. “Carboxyl” is intended to mean the radical —C(O)OH.“Keto” or “oxo” is intended to mean the radical ═O. “Thioketo” isintended to mean the radical ═S. “Carbamoyl” is intended to mean theradical —C(O)NH₂. “Cycloalkylalkyl” is intended to mean the radical-alkyl-cycloalkyl, wherein alkyl and cycloalkyl are defined as above,and is exemplified by the bonding arrangement present in the groups—CH₂-cyclohexane or —CH₂-cyclohexene. “Arylalkyl” is intended to meanthe radical -alkylaryl, wherein alkyl and aryl are defined as above, andis exemplified by the bonding arrangement present in a benzyl group.“Aminocarbonylalkyl” is intended to mean the radical -alkylC(O) NH₂ andis exemplified by the bonding arrangement present in the group—CH₂CH₂C(O)NH₂. “Alkylaminocarbonylalkyl” is intended to mean theradical -alkylC(O)NHR_(a), wherein R_(a) is an alkyl group and isexemplified by the bonding arrangement present in the group—CH₂CH₂C(O)NHCH₃. “Alkylcarbonylaminoalkyl is intended to mean theradical -alkylNHC(O)-alkyl and is exemplified by the bonding arrangementpresent in the group —CH₂NHC(O)CH₃. “Dialkylaminocarbonylalkyl” isintended to mean the radical -alkylC(O)NR_(a)R_(b), wherein R_(a) andR_(b) are each independently an alkyl group. “Aryloxy” is intended tomean the radical —OR_(c), wherein R_(c) is an aryl group.“Heteroaryloxy” is intended to mean the radical —OR_(d), wherein R^(d)is a heteroaryl group. “Arylthio” is intended to mean the radical—SR_(c), wherein R_(c) is an aryl group. “Heteroarylthio” is intended tomean the radical —SR_(d), wherein R_(d) is a heteroaryl group.

[0080] The alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroarylgroups and the substituents containing these groups, as definedhereinabove, may be optionally substituted by at least one othersubstituent. The term “optionally substituted” is intended to expresslyindicate that the specified group is unsubstituted or substituted by oneor more suitable substituents. Various groups may be unsubstituted orsubstituted (i.e., they are optionally substituted) as indicated.

[0081] If the substituents themselves are not compatible with thesynthetic methods of this invention, the substituent may be protectedwith a suitable protecting group that is stable to the reactionconditions used in these methods. The protecting group may be removed ata suitable point in the reaction sequence of the method to provide adesired intermediate or target compound. Suitable protecting groups andthe methods for protecting and de-protecting different substituentsusing such suitable protecting groups are well known to those skilled inthe art; examples of which may be found in T. Greene and P. Wuts,Protecting Groups in Chemical Synthesis (3rd ed.), John Wiley & Sons, NY(1999), which is incorporated herein by reference in its entirety. Insome instances, a substituent may be specifically selected to bereactive under the reaction conditions used in the methods of thisinvention. Under these circumstances, the reaction conditions convertthe selected substituent into another substituent that is either usefulin an intermediate compound in the methods of this invention or is adesired substituent in a target compound.

[0082] Particular embodiments of this invention comprise the compoundsof Formulas II and III, wherein n is 2 or 1, respectively, depicted bythe formula:

[0083] wherein:

[0084] W is CH or N;

[0085] R^(a′) is an alkyl, cycloalkyl, aryl or heteroaryl group, wherethe alkyl, cycloalkyl, aryl, and heteroaryl group is unsubstituted orsubstituted with one or more suitable substituents, provided that R^(a′)is not an amino-substituted alkyl group;

[0086] R⁴ and R⁶ are each independently H or a lower alkyl group;

[0087] R⁵ is H or an alkyl group;

[0088] R⁷ is a substituent having the formula:

[0089] wherein:

[0090] R⁸ and R⁹ are each independently H or lower alkyl;

[0091] p is an integer of from 1 to 5;

[0092] A₁ is CH or N;

[0093] when p is 1, 2, 3, 4, or 5, A₂ is C(R¹⁰)(R¹¹), N(R¹²), S, S(O),S(O)₂, or O, and when p is 0, A₂ is C(R¹⁰)(R¹¹)(R¹²), N(R¹⁰)(R¹²),S(R¹⁰), S(O)(R¹⁰), S(O)₂(R¹⁰), or O(R¹⁰) where each R¹⁰, R¹¹ and R¹² isindependently H or a lower alkyl group;

[0094] each A₃ present is independently C(R¹⁰)(R¹¹), N(R¹²), S, S(O),S(O)₂, or O, where each R¹⁰, R¹¹ and R¹² is independently H or a loweralkyl group;

[0095] when p is 1, 2, 3, 4, or 5, A₄ is N(R¹³), C(R¹⁰)(R¹¹), or O, andwhen p is 0, A₄ is N(R¹³)(R¹⁴), C(R¹⁰)(R¹¹)(R¹²), and O(R¹⁴), where eachR¹⁰, R¹¹ and R¹² is independently H or a lower alkyl group, each R¹³ isH or an alkyl, aryl, or acyl group, and each R¹⁴ is H or an alkyl oraryl group;

[0096] provided that no more than two heteroatoms occur consecutively inthe above-depicted ring formed by A₁, (A₂)_(m), (A₃)_(p), A₄, and C═O,where each dotted line in the ring depicts a single bond when A₂ ispresent and a hydrogen atom when A₂ is absent; and

[0097] Z and Z¹ are each independently H, F, an alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl group, where the alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl group is unsubstituted orsubstituted with one or more suitable substituents, —C(O)R¹⁵, —CO₂R¹⁵,—CN, —C(O)NR¹⁵R¹⁶, —C(O)NR¹⁵OR¹⁶, —C(S)R¹⁵, —C(S)OR⁵, —C(S)NR¹⁵R¹⁶,—C(═NR¹⁵)R¹⁶, —C(═NR¹⁵)OR¹⁶, —NO₂, —SOR¹⁶, —SO₂R¹⁵, —SO₂NR¹⁵R¹⁶,—SO₂(NR¹⁵)(OR¹⁶), —SONR¹⁵, —SO₃R¹⁵, —PO(OR¹⁵)₂, —PO(OR¹⁵)(OR¹⁶),—PO(NR¹⁵R¹⁶)(OR¹⁷), —PO(NR¹⁵R¹⁶)(NR¹⁷R¹⁸), —C(O)NR¹⁵NR¹⁶R¹⁷,—C(S)NR¹⁵NR¹⁶R¹⁷, where R¹⁵, R¹⁶, R¹⁷ and R¹⁸ are each independently Hor an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacyl group,where the alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacylgroup is unsubstituted or substituted with one or more suitablesubstituents, or where any two of the R¹⁵, R¹⁶, R¹⁷ and R¹⁸, takentogether with the atoms to which they are bonded, form aheterocycloalkyl group, which is unsubstituted or substituted with oneor more suitable substituents,

[0098] or Z and Z¹, together with the atoms to which they are bonded,form a cycloalkyl or heterocycloalkyl group, where Z and Z¹ are asdefined above (except for moieties that cannot form the cycloalkyl orheterocycloalkyl group);

[0099] or a prodrug, pharmaceutically acceptable salt, pharmaceuticallyactive metabolite, or pharmaceutically acceptable solvate thereof ofsaid compound.

[0100] More specifically, preferred embodiments of Formula VI of thisinvention comprise the compounds depicted by the formula:

[0101] wherein R^(a′), R⁴, R⁵, R⁶, R⁷, Z and Z¹ are as defined above;and the compounds depicted by the formula:

[0102] wherein R^(a′), R⁴, R⁵, R⁶, R⁷, Z and Z¹ are as defined above.

[0103] In particular, this invention comprises the compounds depicted bythe formula:

[0104] wherein:

[0105] R^(l) is H, halo or an alkoxy, alkyl, aryl, cycloalkyl,heterocycloalkyl or heteroaryl group, where the alkoxy, alkyl, aryl,cycloalkyl, heterocycloalkyl, or heteroaryl group is unsubstituted orsubstituted with one or more suitable substituents;

[0106] R² and R³ are each independently H, halo or an alkoxy or loweralkyl group, where the alkoxy or lower alkyl group is unsubstituted orsubstituted with one or more suitable substituents;

[0107] or R¹ together with R² form a cycloalkyl, heterocycloalkyl, arylor heteroaryl ring, where the cycloalkyl, heterocycloalkyl, aryl orheteroaryl ring is unsubstituted or substituted with one or moresuitable substituents;

[0108] R⁴ and R⁶ are each independently H or a lower alkyl group,unsubstituted or substituted with one or more suitable substituents;

[0109] R⁵ is H or an alkyl group, unsubstituted or substituted with oneor more suitable substituents;

[0110] R⁷ is a moiety having the formula:

[0111] wherein:

[0112] R⁸ and R⁹ are each each independently H or a lower alkyl group;

[0113] m is 0 or 1;

[0114] p is an integer of from 0 to 5;

[0115] A₁ is CH or N;

[0116] when p is 1, 2, 3, 4, or 5, A₂ is C(R¹⁰)(R¹¹), N(R¹²), S, S(O),S(O)₂, or O, and when p is 0, A₂ is C(R¹⁰)(R¹¹)(R¹²), N(R¹⁰)(R¹²),S(R¹⁰), S(O)(R¹⁰), S(O)₂(R¹⁰), or O(R¹⁰) where each R¹⁰, R¹¹ and R¹² isindependently H or a lower alkyl group;

[0117] each A₃ present is independently C(R¹⁰)(R¹¹), N(R¹²), S, S(O),S(O)₂, or O, where each R¹⁰, R¹¹ and R¹² is independently H or a loweralkyl group;

[0118] when p is 1, 2, 3, 4, or 5, A₄ is N(R¹³), C(R¹⁰)(R¹¹), or O, andwhen p is 0, A₄ is N(R¹³)(R¹⁴), C(R¹⁰)(R¹¹)(R¹²), and O(R¹⁴), where eachR¹⁰, R¹¹ and R¹² is independently H or a lower alkyl group, each R¹³ isH or an alkyl, aryl, or acyl group, and each R¹⁴ is H or an alkyl oraryl group;

[0119] provided that no more than two heteroatoms occur consecutively inthe above-depicted ring formed by A₁, (A₂)_(m), (A₃)_(p), A₄, and C═O,where each dotted line in the ring depicts a single bond when A₂ ispresent and a hydrogen atom when A₂ is absent; and

[0120] Z and Z¹ are each independently H, F, an alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl group, where the alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl group is unsubstituted orsubstituted with one or more suitable substituents, —C(O)R¹⁵, —CO₂R¹⁵,—CN, —C(O)NR¹⁵R¹⁶, —C(O)NR¹⁵OR¹⁶, —C(S)R¹⁵, —C(S)OR¹⁵, —C(S)NR¹⁵R¹⁶,—C(═NR¹⁵)R¹⁶, —C(═NR¹⁵)OR¹⁶, —NO₂, —SOR¹⁶, —SO₂R¹⁵, —SO₂NR¹⁵R¹⁶,—SO₂(NR¹⁵)(OR¹⁶), —SONR¹⁵, —SO₃R¹⁵, —PO(OR¹⁵)₂, —PO(OR¹⁵)(OR¹⁶),—PO(NR¹⁵R¹⁶)(OR¹⁷), —PO(NR¹⁵R¹⁶)(NR¹⁷R¹⁸, —C(O)NR¹⁵NR¹⁶R¹⁷,—C(S)NR¹⁵NR¹⁶R¹⁷, where R¹⁵, R¹⁶, R¹⁷ and R¹⁸ are each independently Hor an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacyl group,where the alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacylgroup is unsubstituted or substituted with one or more suitablesubstituents, or where any two of the R¹⁵, R¹⁶, R¹⁷ and R¹⁸, takentogether with the atoms to which they are bonded, form aheterocycloalkyl group, which is unsubstituted or substituted with oneor more suitable substituents,

[0121] or Z and Z¹, together with the atoms to which they are bonded,form a cycloalkyl or heterocycloalkyl group, where Z and Z¹ are asdefined above (except for moieties that cannot form the cycloalkyl orheterocycloalkyl group);

[0122] or a prodrug, pharmaceutically acceptable salt, pharmaceuticallyactive metabolite, or pharmaceutically acceptable solvate of saidcompound.

[0123] Another embodiment of this invention comprises the compoundsdepicted by the formula:

[0124] wherein:

[0125] R¹ is H, halo or an alkoxy, alkyl, aryl, cycloalkyl,heterocycloalkyl, or heteroaryl group, where the alkoxy, alkyl, aryl,cycloalkyl, heterocycloalkyl, or heteroaryl group is unsubstituted orsubstituted with one or more suitable substituents;

[0126] R² and R³ are each independently H, halo or an alkoxy or loweralkyl group, where the alkoxy or lower alkyl group is unsubstituted orsubstituted with one or more suitable substituents;

[0127] or R¹ together with R² form a cycloalkyl, heterocycloalkyl, arylor heteroaryl ring, where the cycloalkyl, heterocycloalkyl, aryl orheteroaryl ring is unsubstituted or substituted with one or moresuitable substituents;

[0128] R⁴ and R⁶ are each independently H or lower alkyl, unsubstitutedor substituted with one or more suitable substituents;

[0129] R⁵ is H or an alkyl group, unsubstituted or substituted with oneor more suitable substituents;

[0130] R⁷ is a moiety having the formula:

[0131] wherein:

[0132] R⁸ and R⁹ are each independently H or a lower alkyl group;

[0133] m is 0 or 1, provided that when m is 0 and R¹ together with R²form an aryl ring, the aryl ring is unsubstituted (e.g., R¹ togetherwith R² and the pyrrole to which they are bound do not form asubstituted indole);

[0134] p is an integer of from 0 to 5;

[0135] A₁ is CH or N;

[0136] when p is 1, 2, 3, 4, or 5, A₂ is C(R¹⁰)(R¹¹), N(R¹²), S, S(O),S(O)₂, or O, and when p is 0, A₂ is C(R¹⁰)(R¹¹)(R¹²), N(R¹⁰)(R¹²),S(R¹⁰), S(O)(R¹⁰), S(O)₂(R¹⁰), or O(R¹⁰) where each R¹⁰, R¹¹ and R¹² isindependently H or a lower alkyl group;

[0137] each A₃ present is independently C(R¹⁰)(R¹¹), N(R¹²), S, S(O),S(O)₂, or O, where each R¹⁰, R¹¹ and R¹² is independently H or a loweralkyl group;

[0138] when p is 1, 2, 3, 4, or 5, A₄ is N(R¹³), C(R¹⁰)(R¹¹), or O, andwhen p is 0, A₄ is N(R¹³)(R¹⁴), C(R¹⁰)(R¹¹)(R¹²), and O(R¹⁴), where eachR¹⁰, R¹¹ and R¹² is independently H or a lower alkyl group, each R¹³ isH or an alkyl, aryl, or acyl group, and each R¹⁴ is H or an alkyl oraryl group;

[0139] provided that no more than two heteroatoms occur consecutively inthe above-depicted ring formed by A₁, (A₂)_(m), (A₃)_(p), A₄, and C═O,where each dotted line in the ring depicts a single bond when A₂ ispresent and a hydrogen atom when A₂ is absent; and

[0140] Z and Z¹ are each independently H, F, an alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl group, where the alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl group is unsubstituted orsubstituted with one or more suitable substituents, —C(O)R¹⁵, —CO₂R¹⁵,—CN, —C(O)NR¹⁵R¹⁶, —C(O)NR¹⁵OR¹⁶, —C(S)R¹⁵, —C(S)OR¹⁵, —C(S)NR¹⁵R¹⁶,—C(═NR¹⁵)R¹⁶, —C(═NR¹⁵)OR¹⁶, —NO₂, —SOR¹⁶, —SO₂R¹⁵, —SO₂NR¹⁵R¹⁶,—SO₂(NR¹⁵)(OR¹⁶), —SONR¹⁵, —SO₃R¹⁵, —PO(OR¹⁵)₂, —PO(OR¹⁵)(OR¹⁶),—PO(NR¹⁵R¹⁶)(OR¹⁷), —PO(NR¹⁵R¹⁶)(NR¹⁷R¹⁸), —C(O)NR¹⁵NR¹⁶R¹⁷,—C(S)NR¹⁵NR¹⁶R¹⁷, where R¹⁵, R¹⁶, R¹⁷ and R¹⁸ are each independently Hor an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacyl group,where the alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacylgroup is unsubstituted or substituted with one or more suitablesubstituents, or where any two of the R¹⁵, R¹⁶, R¹⁷ and R¹⁸, takentogether with the atoms to which they are bonded, form aheterocycloalkyl group, which is unsubstituted or substituted with oneor more suitable substituents,

[0141] or Z and Z¹, together with the atoms to which they are bonded,form a cycloalkyl or heterocycloalkyl group, where Z and Z¹ are asdefined above (except for moieties that cannot form the cycloalkyl orheterocycloalkyl group);

[0142] or a prodrug, pharmaceutically acceptable salt, pharmaceuticallyactive metabolite, or pharmaceutically acceptable solvate of saidcompound.

[0143] In another embodiment of the compounds of the above formulas,

[0144] A₁ is CH or N;

[0145] A₂ is C(R¹⁰)(R¹¹), N(R¹²), S, S(O), S(O)₂, or O, where each R¹⁰,R¹¹ and R¹² is independently H or a lower alkyl group;

[0146] each A₃ present is independently C(R¹⁰)(R¹¹), N(R¹²), S, S(O),S(O)₂, or O, where each R¹⁰, R¹¹ and R¹² is independently H or a loweralkyl group;

[0147] when p is 1, 2, 3, 4, or 5, A₄ is N(R¹³), C(R¹⁰)(R¹¹), or O, andwhen p is 0, A₄ is N(R¹³)(R¹⁴), C(R¹⁰)(R¹¹)(R¹²), and O(R¹⁴), where eachR¹⁰, R¹¹ and R¹² is independently H or a lower alkyl group, each R¹³ isH or an alkyl, aryl, or acyl group, and each R¹⁴ is H or an alkyl oraryl group;

[0148] provided that no more than two heteroatoms occur consecutively inthe above-depicted ring formed by A₁, (A₂)_(m), (A₃)_(p), A₄, and C═O,where each dotted line in the ring depicts a single bond when A₂ ispresent and a hydrogen atom when A₂ is absent; and

[0149] Z and Z¹ are each independently H, F, an alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl group, where the alkyl, aryl,cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is unsubstitutedor substituted with one or more suitable substituents, —C(O)R¹⁵,—CO₂R¹⁵, —CN, —C(O)NR¹⁵R¹⁶, —C(O)NR¹⁵OR¹⁶, —C(S)R¹⁵, —C(S)NR¹⁵R¹⁶, —NO₂,—SOR¹⁶, —SO₂R¹⁵, —SO₂NR¹⁵R¹⁶, —SO₂(NR¹⁵)(OR¹⁶), —SONR¹⁵, —SO₃R¹⁵,—PO(OR¹⁵)₂, —PO(OR¹⁵)(OR¹⁶), —PO(NR¹⁵R¹⁶)(OR¹⁷), —PO(NR¹⁵R¹⁶)(NR¹⁷R¹⁸),—C(O)NR¹⁵NR¹⁶R¹⁷, —C(S)NR¹⁵NR¹⁶R¹⁷, where R¹⁵, R¹⁶, R¹⁷ and R¹⁸ are eachindependently H or an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl orthioacyl group, where the alkyl, aryl, cycloalkyl, aryl,heterocycloalkyl, acyl or thioacyl group is unsubstituted or substitutedwith one or more suitable substituents, or where any two of the R¹⁵,R¹⁶, R¹⁷ and R¹⁸, taken together with the atoms to which they arebonded, form a heterocycloalkyl group, which is unsubstituted orsubstituted with one or more suitable substituents, or Z and Z¹,together with the atoms to which they are bonded, form a cycloalkyl orheterocycloalkyl group, where Z and Z¹ are as defined above. Preferably,in the compounds of Formulas IX and X, R¹ may be selected from H and alower alkyl, phenyl, naphthyl, pyridyl, quinoyl, isoquinoyl or isoxazoylgroup, where the lower alkyl, phenyl, naphthyl, pyridyl, quinoyl,isoquinoyl or isoxazoyl group is unsubstituted or substituted with oneor more substituents selected from alkyl (but not as a substituent foralkyl), hydroxy, halo, haloalkyl, alkoxy, haloalkoxy and alkylenedioxymoiety. Exemplary R¹ groups include, but are not limited to H, phenyl,α-naphthyl, β-naphthyl, 2-chlorophenyl, 2-α,α,α-trifluoromethylphenyl,3-chloro-6-methoxyphenyl, 2,3-dichlorophenyl, 4-isoquinoyl,3-iso-propylphenyl, 2,5-dimethoxyphenyl, 2-methoxyphenyl, 2-methylphenyl(o-tolyl), 2-bromophenyl, 3-pyridyl, 4-pyridyl, 3-methyl-isoxazol-5-yl,3,3,3-trifluoroprop-1-yl, and 2,3-benzo[d]dioxolyl. Preferably, in thecompounds of Formulas IX and X, R² and R³ may be each independentlyselected from H, halo, alkoxy, unsubstituted lower alkyl, haloalkyl, andlower alkoxyalkyl. R⁴ and R⁶ may be each independently selected from H,unsubstituted lower alkyl, haloalkyl and lower alkoxyalkyl.

[0150] Yet another preferred embodiment of this invention comprises thecompounds depicted by the formula:

[0151] wherein:

[0152] each R^(z) is H or a suitable substituent and n_(z) is an integerfrom 1 to 4;

[0153] R⁷ is a moiety having the formula:

[0154] wherein:

[0155] R⁸ and R⁹ are each independently H or a lower alkyl group;

[0156] p is an integer of from 1 to 5;

[0157] A₁ is CH or N;

[0158] when p is 1, 2, 3, 4, or 5, A₂ is C(R¹⁰)(R¹¹), N(R¹²), S, S(O),S(O)₂, or O, and when p is 0, A₂ is C(R¹⁰)(R¹¹)(R¹²), N(R¹⁰)(R¹²),S(R¹⁰), S(O)(R¹⁰), S(O)₂(R¹⁰), or O(R¹⁰) where each R¹⁰, R¹¹ and R¹² isindependently H or a lower alkyl group;

[0159] each A₃ present is independently C(R¹⁰)(R¹¹), N(R¹²), S, S(O),S(O)₂, or O, where each R¹⁰, R¹¹ and R¹² is independently H or a loweralkyl group;

[0160] A₄ is N(R¹³), C(R¹⁰)(R¹¹), or O, where R¹⁰ and R¹¹ are eachindependently H or a lower alkyl group, and R¹³ is H or an alkyl, arylor acyl group;

[0161] provided that no more than two heteroatoms occur consecutively inthe above-depicted ring formed by A₁, (A₂)_(m), (A₃)_(p), A₄, and C═O;and

[0162] each R³, R⁴, R⁵, R⁶, Z and Z¹ are as defined above.

[0163] Preferably, in the compounds of Formula XI, each R^(z) isindependently selected from H, halo, alkoxy, unsubstituted lower alkyl,haloalkyl, and lower alkoxyalkyl. R³ may be independently selected fromH, halo, alkoxy, unsubstituted lower alkyl, haloalkyl and loweralkoxyalkyl and R⁴ and R⁶ may be each independently selected from H,unsubstituted lower alkyl, haloalkyl and lower alkoxyalkyl.

[0164] Another preferred embodiment of this invention comprise thecompounds of Formula IV, wherein n is 1, depicted by the formula:

[0165] wherein:

[0166] R^(a′) is an alkyl, aryl, cycloalkyl, heterocycloalkyl orheteroaryl, where the alkyl, aryl, cycloalkyl, heterocycloalkyl, orheteroaryl group is unsubstituted or substituted with one or moresuitable substituents;

[0167] R⁵ is H or an alkyl group, unsubstituted or substituted with oneor more suitable substituents;

[0168] each R⁶ is independently H or a lower alkyl group, unsubstitutedor substituted with one or more suitable substituents;

[0169] R⁷ is a moiety having the formula:

[0170] wherein:

[0171] R⁸ and R⁹ are each independently H or a lower alkyl group;

[0172] m is 0 or 1;

[0173] p is an integer of from 0 to 5;

[0174] A₁ is CH or N;

[0175] when p is 1, 2, 3, 4, or 5, A₂ is C(R¹⁰)(R¹¹), N(R¹²), S, S(O),S(O)₂, or O, and when p is 0, A₂ is C(R¹⁰)(R¹¹)(R¹²), N(R¹⁰)(R¹²),S(R¹⁰), S(O)(R¹⁰), S(O)₂(R¹⁰), or O(R¹⁰) where each R¹⁰, R¹¹ and R¹² isindependently H or a lower alkyl group;

[0176] each A₃ present is independently C(R¹⁰)(R¹¹), N(R¹²), S, S(O),S(O)₂, or O, where each R¹⁰, R¹¹ and R¹² is independently H or a loweralkyl group;

[0177] when p is 1, 2, 3, 4, or 5, A₄ is N(R¹³), C(R¹⁰)(R¹¹), or O, andwhen p is 0, A₄ is N(R¹³)(R¹⁴), C(R¹⁰)(R¹¹)(R¹²), and O(R¹⁴), where eachR¹⁰, R¹¹ and R¹² is independently H or a lower alkyl group, each R¹³ isH or an alkyl, aryl, or acyl group, and each R¹⁴ is H or an alkyl oraryl group;

[0178] provided that no more than two heteroatoms occur consecutively inthe above-depicted ring formed by A₁, (A₂)_(m), (A₃)_(p), A₄, and C═O,where each dotted line in the ring depicts a single bond when A₂ ispresent and a hydrogen atom when A₂ is absent; and

[0179] Z and Z¹ are each independently H, F, an alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl group, where the alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl group is unsubstituted orsubstituted with one or more suitable substituents, —C(O)R¹⁵, —CO₂R¹⁵,—CN, —C(O)NR¹⁵R¹⁶, —C(O)NR¹⁵OR¹⁶, —C(S)R¹⁵, —C(S)OR¹⁵, —C(S)NR¹⁵R¹⁶,—C(═NR¹⁵)R¹⁶, —C(═NR¹⁵)OR¹⁶, —NO₂, —SOR¹⁶, —SO₂R¹⁵, —SO₂NR¹⁵R¹⁶,—SO₂(NR¹⁵)(OR¹⁶), —SONR¹⁵, —SO₃R¹⁵, —PO(OR¹⁵)₂, —PO(OR¹⁵)(OR¹⁶),—PO(NR¹⁵R¹⁶)(OR¹⁷), —PO(NR¹⁵R¹⁶)(NR¹⁷R¹⁸), —C(O)NR¹⁵NR¹⁶R¹⁷,—C(S)NR¹⁵NR¹⁶R¹⁷, where R¹⁵, R¹⁶, R¹⁷ and R¹⁸ are each independently Hor an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacyl group,where the alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacylgroup is unsubstituted or substituted with one or more suitablesubstituents, or where any two of the R¹⁵, R¹⁶, R¹⁷ and R¹⁸, takentogether with the atoms to which they are bonded, form aheterocycloalkyl group, which is unsubstituted or substituted with oneor more suitable substituents,

[0180] or Z and Z¹, together with the atoms to which they are bonded,form a cycloalkyl or heterocycloalkyl group, where Z and Z¹ are asdefined above (except for moieties that cannot form the cycloalkyl orheterocycloalkyl group);

[0181] or a prodrug, pharmaceutically acceptable salt, pharmaceuticallyactive metabolite, or pharmaceutically acceptable solvate of saidcompound.

[0182] In another embodiment of the compounds of the above formulas, Zand Z¹ are each independently H, F, an alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl group, where the alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl group is unsubstituted orsubstituted with one or more suitable substituents, —C(O)R¹⁵, —CO₂R¹⁵,—CN, —C(O)NR¹⁵R¹⁶, —C(O)NR¹⁵OR¹⁶, —C(S)R¹⁵, —C(S)NR¹⁵R¹⁶, —NO₂, —SOR¹⁶,—SO₂R¹⁵, —SO₂NR¹⁵R¹⁶, —SO₂(NR¹⁵)(OR¹⁶), —SONR¹⁵, —SO₃R¹⁵, —PO(OR¹⁵)₂,—PO(OR¹⁵)(OR¹⁶), —PO(NR¹⁵R¹⁶)(OR¹⁷), —PO(R¹⁵R¹⁶)(NR¹⁷R¹⁸),—C(O)NR¹⁵NR¹⁶R¹⁷, —C(S)NR¹⁵NR¹⁶R¹⁷, where R¹⁵, R¹⁶, R¹⁷ and R¹⁸ areindependently H or an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl orthioacyl group, where the alkyl, cycloalkyl, aryl, heterocycloalkyl,acyl or thioacyl group is unsubstituted or substituted with one or moresuitable substituents, or where any two of the R¹⁵, R¹⁶, R¹⁷ and R¹⁸,taken together with the atoms to which they are bonded, form aheterocycloalkyl group, which is unsubstituted or substituted with oneor more suitable substituents, or Z and Z¹, together with the atoms towhich they are bonded, form a cycloalkyl or heterocycloalkyl group,where Z and Z¹ are as defined above.

[0183] Preferably, in the compounds of Formula XII, R^(a′) may beselected from H, lower alkyl, phenyl, naphthyl, pyridyl, quinoyl,isoquinoyl and isoxazoyl, each of which may be substituted by alkyl (butnot as a substituent for alkyl), hydroxy, halo, haloalkyl, alkoxy,haloalkoxy and alkylenedioxy. Each R⁶ may be independently selected fromH, unsubstituted lower alkyl, haloalkyl and loweralkoxyalkyl.

[0184] If an inventive compound is a base, a desired salt may beprepared by any suitable method known in the art, including treatment ofthe free base with an inorganic acid, such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike, or with an organic acid, such as acetic acid, maleic acid,succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid,oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid, such asglucuronic acid or galacturonic acid, alpha-hydroxy acid, such as citricacid or tartaric acid, amino acid, such as aspartic acid or glutamicacid, aromatic acid, such as benzoic acid or cinnamic acid, sulfonicacid, such as p-toluenesulfonic acid or ethanesulfonic acid, or thelike.

[0185] If an inventive compound is an acid, a desired salt may beprepared by any suitable method known to the art, including treatment ofthe free acid with an inorganic or organic base, such as an amine(primary, secondary, or tertiary); an alkali metal or alkaline earthmetal hydroxide; or the like. Illustrative examples of suitable saltsinclude organic salts derived from amino acids such as glycine andarginine; ammonia; primary, secondary, and tertiary amines; and cyclicamines, such as piperidine, morpholine, and piperazine; as well asinorganic salts derived from sodium, calcium, potassium, magnesium,manganese, iron, copper, zinc, aluminum, and lithium.

[0186] All compounds of this invention contain at least one chiralcenter and may exist as single stereoisomers (e.g., single enantiomersor diastereomers), any mixture of stereosisomers (e.g., any mixture ofenantiomers or diastereomers) or racemic mixtures thereof. All suchsingle stereoisomers, mixtures and racemates are intended to beencompassed within the broad scope of the present invention. Where thestereochemistry of the chiral carbons present in the chemical structuresillustrated herein is not specified, the chemical structure is intendedto encompass compounds containing either stereoisomer of each chiralcarbon. When used describe a particular compound, the term “opticallypure” is used herein to indicate that the compound is substantiallyenantiomerically or diastereomerically pure. Compounds that aresubstantially enatiomerically pure contain at least 90% of a singleisomer and preferably contain at least 95% of a single isomer. Compoundsthat are substantially diastereomerically pure contain at least 90% of asingle isomer of each chiral carbon center present in the diastereomer,and preferably contain at least 95% of a single isomer of each chiralcarbon. More preferably, when an optically active compound is desired,it contains at least 97.5% of a single isomer and, most preferably, atleast 99% of the single isomer. Compounds identified herein as singlestereoisomers are meant to describe compounds that are present in a formthat contains at least 90% of a single isomer. The term “racemic” or“racemic mixture” refers to a mixture of equal amounts of enantiomericcompounds, which encompasses mixtures of enantiomers and mixtures ofenantiomeric diastereomers. The compounds of this invention may beobtained in stereochemically (e.g., enantiomerically ordiastereomerically) pure or substantially stereochemically pure form.Such compounds may be obtained synthetically, according to theprocedures described herein using optically pure or substantiallyoptically pure materials. Alternatively, these compounds may be obtainedby resolution/separation of a mixture of stereoisomers, includingracemic mixtures, using conventional procedures. Exemplary methods thatmay be useful for the resolution/separation of stereoisomeric mixturesinclude chromatography and crystallization/re-crystallization. Otheruseful methods may be found in “Enantiomers, Racemates, andResolutions,” J. Jacques et al., 1981, John Wiley and Sons, New York,N.Y. Preferred stereoisomers of the compounds of this invention aredescribed herein.

[0187] In especially preferred embodiments of Formulas V, VI, VII, VIII,IX, X, XI and XII, R⁵ (or R^(x) or R^(y) in Formulas II, III and VI) isH or an unsubstituted alkyl group or an optionally substituted loweralkyl group, where these groups are comprised of a straight- orbranched-chain saturated hydrocarbon group, a straight- orbranched-chain substituted saturated hydrocarbon group, or groupcomprised of a straight- or branched-chain saturated hydrocarbon moietyand an unsaturated hydrocarbon moiety. When R⁵ or R^(x)/R^(y) is asubstituted alkyl group, the point of attachment of R⁵ or R^(x)/R^(y) isvia a saturated hydrocarbon moiety. When R⁵ or R^(x)/R^(y) is asubstituted saturated hydrocarbon group, the saturated hydrocarbon groupmay be optionally substituted with a cycloalkyl group, aheterocycloalkyl group, an aryl group, a heteroaryl group, an alkoxygroup, an aryloxy group, an alkylthio group, an arylthio group, whereeach alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl moietythereof may be optionally substituted. When R⁵ or R^(x)/R^(y) iscomprised of a saturated hydrocarbon moiety and an unsaturatedhydrocarbon moiety, the saturated hydrocarbon moiety may be bound to anunsaturated hydrocarbon moiety containing one or more double-bonds ortriple-bonds, the terminal positions of which may be substituted by thesubstituents described above, or may contain additional straight- orbranched-chain saturated hydrocarbon moieties. Preferably, theunsaturated hydrocarbon moiety contains one double-bond or onetriple-bond, the terminal position(s) of which may optionally contain astraight- or branched-chain saturated hydrocarbon moiety. Preferably, ifthe unsaturated hydrocarbon moiety contains a double-bond, both terminalpositions of the double bond contain a straight- or branched-chainsaturated hydrocarbon moiety. In especially preferred embodiments, R⁵ orR^(x)/R^(y) is H or a lower alkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl group, or a group comprised of a straight-chainsaturated hydrocarbon moiety and an unsaturated hydrocarbon moiety,where the alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl group isunsubstituted or substituted with one or more suitable substituents.Preferably, R⁵ or R^(x)/R^(y) is H or substituted or unsubstitutedmethyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl,-methylcyclohexyl, substituted or unsubstituted -methylthienyl orsubstituted or unsubstituted benzyl, where the methyl, ethyl, propyl,propenyl, butenyl or cyclohexyl moiety thereof is optionally substitutedwith one or more substituents independently selected from lower alkoxy,hydroxy, amino, alkylamino or dialkylamino and halogen, the phenylmoiety of the substituted benzyl is substituted by one or moresubstituents independently selected from lower alkyl, lower alkoxy,hydroxy, amino, alkylamino or dialkylamino and halogen and the thienylmoiety of the substituted -methylthienyl is substituted by one or moresubstituents independently selected from lower alkyl, lower alkoxy,hydroxy, amino, alkylamino, dialkylamino and halogen. When R⁵ orR^(x)/R^(y) is substituted methyl, the methyl (methylene) moiety may besubstituted with an alkoxy group, an aryloxy group, an alkylthio groupor an arylthio group. Most preferably, R⁵ or R^(x)/R^(y) is H, ethyl,2-propyn-1-yl, -methylcyclohexyl, or substituted or unsubstitutedbenzyl, where the phenyl moiety of the substituted benzyl is substitutedby one or more substituents independently selected from lower alkyl,lower alkoxy and halogen.

[0188] In the especially preferred embodiments of Formulas V, VI, VII,VIII, XI, X XI and XII, R⁵ (or R^(x) or R^(y) in Formulas II, III andVI) is selected from H and:

[0189] wherein R′ may be H or alkyl and each R″ may be H orindependently selected from lower alkyl, lower alkoxy, hydroxy, amino,alkylamino or dialkylamino, and halogen.

[0190] In especially preferred embodiments of Formulas V, VI, VII, VIII,IX, X, XI and XII, R⁷ (or R^(c) in Formulas I, II, III and VI) isselected from —CH₂CH₂C(O)NH₂; —CH₂CH₂C(O)NH-alkyl; —CH₂NHC(O)CH₃; and

[0191] where n is 1 or 2. More preferably, R⁷ is

[0192] Preferably, in each of the formulas described herein, Z and Z¹are each independently H, alkyl, where the alkyl is unsubstituted orsubstituted with one or more suitable substituents, —CO₂R¹⁵ (in FormulasV to XII) or —CO₂R¹ (in Formulas I to VI), where R¹ and R¹⁵ are asdefined above, or Z and Z¹, taken together with the atom to which theyare attached, form a heterocycloalkyl group, as defined above, which maybe optionally substituted. In one useful embodiment of the compounds ofthis invention, Z and/or Z¹ may be —C(S)OR^(n) or —C(S)OR¹⁹, where R^(n)and R¹⁹ are as defined above. Such compounds may be prepared usingprocedures described in K. Hartke, et al., Leibigs Ann. Chem., 321-330(1989) and K. Hartke, et al., Synthesis, 960-961(1985). More preferably,the heterocycloalkyl group may optionally contain O, N, S and/or P andmay be substituted by one or more of oxo (keto) or thioketo. In anotherpreferred embodiment of this invention, Z and Z¹ are each independentlyselected from H, lower alkyl which is unsubstituted or substituted withone or more suitable substituents, —CO₂H, —CO₂-alkyl and—CO₂-cycloalkyl, or taken together with the atom to which they areattached form a heterocycloalkyl group , which is optionally substitutedwith one or more of keto or thioketo. In other preferred embodiments ofthis invention, Z and Z¹ are not both H. Most preferably, Z¹ is H orlower alkyl and Z is a —CO₂H, —CO₂-alkyl, —CO₂-alkylaryl,—CO₂-alkylheteroaryl, —CO₂-cycloalkyl group, where the lower alkyl,-alkyl, -cycloalkyl, -alkylaryl and -alkylheteroaryl moieties thereofare unsubstituted or substituted with one or more suitable substituents,or Z¹ and Z taken together with the atom to which they are attached forma heterocycloalkyl group, which may be optionally substituted. ExemplaryZ groups include, but are not limited to: substituted and unsubstituted—CO₂-alkyl groups, which include straight- and branched-chain alkylgroups such as ethoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl and(2,2-dimethylpropyl)-oxycarbonyl, where the ethoxy, t-butoxy,isopropoxy, and (2,2-dimethylpropyl)-oxy moieties thereof areunsubstituted or substituted with one or more suitable substituents; andinclude substituted and unsubstituted straight and branched-chainarylalkyl and heteroarylalkyl groups, such as benzyloxycarbonyl andpyridylmethyleneoxycarbonyl, where the benzyl and pyridylmethylenemoieties thereof are unsubstituted or substituted with one or moresuitable substituents; and include substituted and unsubstituted—CO₂-cycloalkyl groups such as cyclobutyloxycarbonyl,cyclopentyloxycarbonyl, cyclohexyloxycarbonyl and cycloheptyloxycarbonylgroups, where the cyclobutyl, cyclopentyl, cyclohexyl and cycloheptylmoieties thereof are unsubstituted or substituted with one or moresuitable substituents, or Z¹ and Z taken together with the atom to whichthey are attached form

[0193] in Formulas V to XII (or

[0194] in Formulas I to VI).

[0195] In another embodiment of this invention, Z¹ is H and Z is—CO₂CH₂CH₃, —CO₂(CH(CH₃)₂), —CO₂(C(CH₃)₃), —CO₂CH₂(C(CH₃)₃),—CO₂(cyclo-C₅H₉) or Z¹ and Z taken together with the atom to which theyare attached form

[0196] In yet another embodiment of this invention, Z¹ is H and Z isselected from ethoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl,(2,2-dimethylpropyl)-oxycarbonyl, benzyloxycarbonyl,pyridylmethyleneoxycarbonyl, cyclobutyloxycarbonyl,cyclopentyloxycarbonyl, cyclohexyloxycarbonyl andcycloheptyloxycarbonyl, or Z¹ and Z taken together with the atom towhich they are attached form

[0197] In the compounds of each of the above-described Formulas, R^(c)and R⁷ are defined to provide structures where m is 1 and p is 1-5(i.e., both A₂ and A₃ are present), m is 0 and p is 0 (i.e, both A₂ andA₃ are absent), m is 0 and p is 1-5 (i.e, A₂ is absent and A₃ ispresent) and m is 1 and p is 0 (i.e, A₂ is present and A₃ is absent).Accordingly, one of ordinary skill in the are will recognize that whenboth A₂ and A₃ are present (m is 1 and p is 1-5), the dotted linebetween A₁ and A₂ represents a bond and the dotted line between A₂ andA₃ represents a bond and when both A₂ and A₃ are absent (m is 0 and p is0); A₂, A₃ and the dotted line between these substituents are notpresent), the remaining dotted line in the structure between A₁ and A₂represents a hydrogen (e.g., A₁ is CH₂ or NH). In embodiments of thisinvention when A₂ is absent and A₃ is present (m is 0 and p is 1-5), thedotted line between A₁ and A₂ represents a hydrogen and the dotted linebetween A₂ and A₃ represents a hydrogen (e.g., A₁ is CH₂ or NH and A₃ isCH(R^(g))(R^(h)), NH(R^(i)), SH, S(O)H, S(O)₂H, or OH or CH(R¹⁰)(R¹¹),NH(R¹²), SH, S(O)H, S(O)₂H, or OH); and when A₂ is present and A₃ isabsent (m is 1 and p is 0), the dotted line between A₁ and A₂ representsa bond and A₂ is C(R^(g))(R^(h))(R^(i)), N(R^(g))(R^(i)), S(R^(g)),S(O)(R^(g)), S(O)₂(R^(g)), or O(R^(g)) or A₂ is C(R¹⁰)(R¹¹)(R¹²),N(R¹⁰)(R¹²), S(R¹⁰), S(O)(R¹⁰), S(O)₂(R¹⁰), or O(R¹⁰) or the dotted linebetween A₂ and A₃ represents a hydrogen and A₂ is CH(R^(g))(R^(h)),NH(R^(i)), SH, S(O)H, S(O)₂H, or OH or A₂ is CH(R¹⁰)(R¹¹), NH(R¹²), SH,S(O)H, S(O)₂H, or OH. In preferred embodiments of the compounds of eachof the above-described Formulas, m is 1 and p is 1 or 2 or m is 0 and pis 0 or m is 1 and p is 0. More preferably, when m is 1 and p is 1 or 2,A₂ and A₃ are both C(R^(g))(R^(h)) or C(R¹⁰)(R¹¹), respectively. Morepreferably, m is 1 and p is 1.

[0198] In the compounds of Formulas I to IV, R^(d) and each R^(b) arepreferably H, in the compounds of Formulas V to XI, each R⁴ and R⁶ arepreferably H and in the compounds of Formula XIII, each R⁶ is preferablyH.

[0199] Other embodiments of this invention comprise compounds having theformula:

[0200] wherein:

[0201] R^(a) is (C₁-C₄)alkylcarbonyl-(C₁-C₄)alkyl,(C₃-C₈)cycloalkylcarbonyl-(C₁-C₄)alkyl, arylcarbonyl-(C₁-C₄)alkyl,heteroarylcarbonyl-(C₁-C₄)alkyl, (C₁-C₄)alkylcarbonylamino-(C₁-C₄)alkyl,(C₃-C₈) cycloalkylcarbonylamino-(C₁-C₄)alkyl,heterocycloalkylcarbonylamino-(C₁-C₄)alkyl,arylcarbonylamino-(C₁-C₄)alkyl, heteroarylcarbonylamino-(C₁-C₄)alkyl,(C₁-C₄ alkylaminocarbonyl-(C₁-C₄)alkyl,(C₃-C₈)cycloalkylaminocarbonyl-(C₁-C₄)alkyl,heterocycloalkylaminocarbonyl-(C₁-C₄)alkyl,arylaminocarbonyl-(C₁-C₄)alkyl, heteroarylaminocarbonyl-(C₁-C₄)alkyl,wherein each (C₁-C₄)alkyl, (C₃-C₈)cycloalkyl, heterocycloalkyl, aryl andheteroaryl moiety thereof is unsubstituted or substituted with one ormore suitable substituents; preferably R^(a) is(C₁-C₄)alkylcarbonyl-(C₁-C₄)alkyl,(C₅-C₆)cycloalkylcarbonyl-(C₁-C₄)alkyl, arylcarbonyl-(C₁-C₄)alkyl,heteroarylcarbonyl-(C₁-C₄)alkyl, (C₁-C₄)alkylcarbonylamino-(C₁-C₄)alkyl,C₃-C₈ cycloalkylcarbonylamino-(C₁-C₄)alkyl,heterocycloalkylcarbonylamino-(C₁-C₄)alkyl,arylcarbonylamino-(C₁-C₄)alkyl, heteroarylcarbonylamino-(C₁-C₄)alkyl,(C₁-C₄alkylaminocarbonyl-(C₁-C₄)alkyl,(C₅-C₆)cycloalkylaminocarbonyl-(C₁-C₄)alkyl,heterocycloalkylaminocarbonyl-(C₁-C₄)alkyl,arylaminocarbonyl-(C₁-C₄)alkyl, heteroarylaminocarbonyl-(C₁-C₄)alkyl,wherein each (C₁-C₄)alkyl, (C₃-C₈)cycloalkyl, heterocycloalkyl, aryl andheteroaryl moiety thereof is unsubstituted or substituted with one ormore suitable substituents; more preferably, R^(a) is(C₁-C₄)alkylcarbonyl-(C₁-C₄)alkyl, phenylcarbonyl-(C₁-C₄)alkyl,naphthylcarbonyl-(C₁-C₄)alkyl, pyrrolylcarbonyl-(C₁-C₄)alkyl,indolylcarbonyl-(C₁-C₄)alkyl, (C₁-C₄)alkylcarbonylamino-(C₁-C₄)alkyl,pyrrolylcarbonylamino-(C₁-C₄)alkyl, indolylcarbonylamino-(C₁-C₄)alkyl,phenylcarbonylamino-(C₁-C₄)alkyl, naphthylcarbonylamino-(C₁-C₄)alkyl,(C₁-C₄)alkylaminocarbonyl-(C₁-C₄)alkyl,pyrrolylaminocarbonyl-(C₁-C₄)alkyl, phenylaminocarbonyl-(C₁-C₄)alkyl,naphthylaminocarbonyl-(C₁-C₄)alkyl, wherein each (C₁-C₄)alkyl, phenyl,naphthyl, pyrrolyl, and indolyl moiety thereof is unsubstituted orsubstituted with one or more substituents independently selected fromhalo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy,methylenedioxy, aryl, heterocycloalkyl, and heteroaryl, where the aryl,heterocycloalkyl or heteroaryl is unsubstituted or substituted by oneore more substituents independently selected from halo, C₁-C₄ alkyl,C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy and methylenedioxy; andpreferably, where said indolyl moiety thereof is substituted with one ortwo substituents independently selected from halo, C₁-C₄ alkoxy,unsubstituted C₁-C₄ alkyl and C₁-C₄ haloalkyl;

[0202] R^(b) and R^(d) are each independently H or C₁-C₄ alkyl;preferably R^(b) and R^(d) are each H;

[0203] R^(c) is selected from —CH₂CH₂C(O)NH₂; —CH₂CH₂C(O)NH-alkyl;—CH₂NHC(O)CH₃; and

[0204] where n is 1 or 2; preferably R^(c) is —CH₂CH₂C(O)NH₂ or

[0205] where n is 1; more preferably, R^(c) is —CH₂CH₂C(O)NH₂ or

[0206] and

[0207] Z¹ is H or C₁-C₄ alkyl and Z is —CO₂-alkyl, —CO₂-cycloalkyl,—CO₂-alkylaryl or —CO₂-alkylheterocycloaryl, or Z¹ and Z taken togetherwith the atom to which they are attached form

[0208] preferably, Z¹ is H and Z is —CO₂CH₂CH₃, —CO₂(CH(CH₃)₂),—CO₂(C(CH₃)₃), —CO₂CH₂(C(CH₃)₃), —CO₂(cyclo-C₅H₉) or Z¹ and Z takentogether with the atom to which they are attached form

[0209] more preferably Z¹ is H and Z is —CO₂CH₂CH₃ or Z¹ and Z takentogether with the atom to which they are attached form

[0210] provided that R^(c) is

[0211] where n is 1 or 2, when R^(a) is anindolylcarbonylamino-(C₁-C₄)alkyl group where the indolyl moiety thereofis substituted with one or more suitable substituents or R^(a) is is notan amino-substituted (C₁-C₄)alkylcarbonylamino-(C₁-C₄)alkyl or R^(a) isis not an amino-substituted (C₁-C₄)alkylcarbonyl-(C₁-C₄)alkyl; and R^(c)is selected from —CH₂CH₂C(O)NH₂; —CH₂CH₂C(O)NH-alkyl; —CH₂NHC(O)CH₃; and

[0212] where n is 1 or 2, when R^(a) is anindolylcarbonylamino-(C₁-C₄)alkyl group where the indolyl moiety thereofis unsubstituted or R^(a) is a (C₁-C₄) alkylaminocarbonyl-(C₁-C₄)alkyl,(C₃-C₈)cycloalkylaminocarbonyl-(C₁-C₄)alkyl,heterocycloalkylaminocarbonyl-(C₁-C₄)alkyl,arylaminocarbonyl-(C₁-C₄)alkyl, heteroarylaminocarbonyl-(C₁-C₄)alkyl, orheteroarylcarbonylamino-(C₁-C₄)alkyl group, wherein each (C₁-C₄)alkyl,(C₃-C₈)cycloalkyl, heterocycloalkyl, aryl and heteroaryl moiety thereofis unsubstituted or substituted with one or more suitable substituents;

[0213] or a prodrug, pharmaceutically acceptable salt, pharmaceuticallyactive metabolite, or pharmaceutically acceptable solvate of saidcompound.

[0214] Preferably, in the compounds of Formula I, as defined above,R^(c) is

[0215] where n is 1, when R^(a) is an indolylcarbonylamino-(C₁-C₄)alkylgroup where the indolyl moiety thereof is substituted with one or twosubstituents independently selected from halo, C₁-C₄ alkoxy,unsubstituted C₁-C₄ alkyl and C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy,methylenedioxy, aryl, heterocycloalkyl, and heteroaryl where the aryl,heterocycloalkyl and heteroaryl is unsubstituted or substituted by oneore more substituents independently selected from halo, C₁-C₄ alkyl,C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy and methylenedioxy; andR^(c) is selected from —CH₂CH₂C(O)NH₂; —CH₂CH₂C(O)NH-alkyl;—CH₂NHC(O)CH₃; and

[0216] where n is 1, when R^(a) is (C₁-C₄)alkylcarbonyl-(C₁-C₄)alkyl,(C₅-C₆)cycloalkyl carbonyl-(C₁-C₄)alkyl, arylcarbonyl-(C₁-C₄)alkyl,heteroarylcarbonyl-(C₁-C₄)alkyl, (C₁-C₄)alkylcarbonylamino-(C₁-C₄)alkyl,C₃-C₈ cycloalkylcarbonylamino-(C₁-C₄)alkyl,heterocycloalkylcarbonylamino-(C₁-C₄)alkyl,arylcarbonylamino-(C₁-C₄)alkyl, heteroarylcarbonylamino-(C₁-C₄)alkyl,(C₁-C₄alkylaminocarbonyl-(C₁-C₄)alkyl,(C₃-C₈)cycloalkylaminocarbonyl-(C₁-C₄)alkyl,heterocycloalkylaminocarbonyl-(C₁-C₄)alkyl,arylaminocarbonyl-(C₁-C₄)alkyl, heteroarylaminocarbonyl-(C₁-C₄)alkyl,wherein each (C₁-C₄)alkyl, (C₃-C₈)cycloalkyl, heterocycloalkyl, aryl andheteroaryl moiety thereof unsubstituted or substituted with one or moresuitable substituents.

[0217] More preferably, in the compounds of Formula I, as defined above,R^(c) is

[0218] when R^(a) is an indolylcarbonylamino-(C₁-C₄)alkyl group wherethe indolyl moiety thereof is substituted with one or two substituentsindependently selected from halo, C₁-C₄ alkoxy, unsubstituted C₁-C₄alkyl and C₁-C₄ haloalkyl; and and R^(c) is —CH₂CH₂C(O)NH₂ or

[0219] when R^(a) is (C₁-C₄)alkylcarbonyl-(C₁-C₄)alkyl,phenylcarbonyl-(C₁-C₄)alkyl, naphthylcarbonyl-(C₁-C₄)alkyl,pyrrolylcarbonyl-(C₁-C₄)alkyl, indolylcarbonyl-(C₁-C₄)alkyl,(C₁-C₄)alkylcarbonylamino-(C₁-C₄)alkyl,pyrrolylcarbonylamino-(C₁-C₄)alkyl, indolylcarbonylamino-(C₁-C₄)alkyl,phenylcarbonylamino-(C₁-C₄)alkyl, naphthylcarbonylamino-(C₁-C₄)alkyl,(C₁-C₄)alkylaminocarbonyl-(C₁-C₄)alkyl,phenylaminocarbonyl-(C₁-C₄)alkyl, naphthylaminocarbonyl-(C₁-C₄)alkyl,wherein each (C₁-C₄)alkyl, phenyl, naphthyl and pyrrolyl moiety thereofis group is unsubstituted or substituted with one or more substituentsindependently selected from halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, C₁-C₄ haloalkoxy, methylenedioxy, aryl, heterocycloalkyl, andheteroaryl, where the aryl, heterocycloalkyl and heteroaryl isunsubstituted or substituted by one ore more substituents independentlyselected from halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄haloalkoxy and methylenedioxy; and said indolyl moiety is unsubstituted.

[0220] Other specific compounds of this invention have the formula:

[0221] R^(a′) is a (C₁-C₄)alkyl, (C₃-C₈)cycloalkyl, aryl or heteroarylgroup, wherein the (C₁-C₄)alkyl, (C₃-C₈)cycloalkyl, aryl and heteroarylgroup is unsubstituted or substituted with one or more substituentsindependently selected from (C₁-C₄)alkyl, aryl, (C₃-C₈)cycloalkyl,heterocycloalkyl, heteroaryl, halo, hydroxyl, (C₁-C₄)alkoxy,alkylenedioxy (as a substituent for aryl or heteroaryl), aryloxy,(C₃-C₈)cycloalkoxy, heteroaryloxy, and carboxyl where the (C₁-C₄)alkyl,aryl, (C₃-C₈)cycloalkyl, heterocycloalkyl, heteroaryl moieties thereofare optionally substituted by one or more of (C₁-C₄)alkyl (except foralkyl), halo, (C₁-C₄)haloalkyl, (C₁-C₄)alkoxy, (C₁-C₄)haloalkoxy,alkylenedioxy, aryl or heteroaryl, where the aryl or heteroaryl isunsubstituted or substituted with one or more substituents independentlyselected from alkyl, haloalkyl, alkylenedioxy, nitro, amino,hydroxamino, alkylamino, dialkylamino, halo, hydroxyl, alkoxy,haloalkoxy, aryloxy, mercapto, alkylthio or arylthio groups; preferably,R^(a′) is a (C₁-C₄)alkyl, pyrrolyl, indolyl, phenyl or naphthyl group,where the (C₁-C₄)alkyl group is unsubstituted or substituted with one ormore substituents independently selected from halo, C₁-C₄ alkoxy orC₁-C₄ haloalkoxy and the pyrrolyl, indolyl, phenyl or naphthyl group isunsubstituted or substituted with one or more substituents independentlyselected from halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄haloalkoxy, methylenedioxy, aryl, heterocycloalkyl and heteroaryl, wherethe aryl, heterocycloalkyl and heteroaryl is unsubstituted orsubstituted by one or more substituents independently selected fromhalo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy andmethylenedioxy; more preferably, R^(a′) is an unsubstituted(C₁-C₄)alkyl, or a pyrrolyl, indolyl, phenyl or naphthyl group, wherethe pyrrolyl, indolyl, phenyl or naphthyl group is unsubstituted orsubstituted by one or more substituents independently selected fromhalo, C₁-C₄ alkyl, C₁-C₄ haloalkyl or a phenyl, naphthyl, isoxazolyl,pyridyl, quinoyl or isoquinoyl group, where the phenyl, naphthyl,isoxazolyl, pyridyl, quinoyl or isoquinoyl group is unsubstituted orsubstituted with one or more substituents independently selected fromhalo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy andmethylenedioxy; in specific embodiments, R^(a′) is an unsubstituted(C₁-C₄)alkyl, pyrrolyl, indolyl, phenyl or naphthyl group or a pyrrolylgroup substituted by phenyl, α-naphthyl, β-naphthyl, 2-chlorophenyl,2-α,α,α-trifluoromethylphenyl, 3-chloro-6-methoxyphenyl,2,3-dichlorophenyl, 4-isoquinoyl, 3-iso-propylphenyl,2,5-dimethoxyphenyl, 2-methoxyphenyl, 2-methylphenyl (o-tolyl),2-bromophenyl, 3-pyridyl, 4-pyridyl, 3-methyl-isoxazol-5-yl,3,3,3-trifluoroprop-1-yl, or 2,3-benzo[d]dioxolyl or an indolyl groupsubstituted by halo, C₁-C₄ alkoxy, unsubstituted C₁-C₄ alkyl, C₁-C₄haloalkyl, and C₁-C₄ alkoxyalkyl;

[0222] n is 1, 2 or 3; preferably n is 1 or 2; more preferably, n is 2;

[0223] R^(x) is H and R^(y) is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl or anarylalkyl, heteroarylalkyl, cycloalkylalkyl group or a straight-chainsaturated hydrocarbon moiety or an unsaturated hydrocarbon moiety, wherethe arylalkyl, heteroarylalkyl, cycloalkylalkyl group is unsubstitutedor substituted with one or more suitable substituents; preferably, R^(x)is H and R^(y) is substituted or unsubstituted methyl, ethyl, n-propyl,iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl,2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, -methylthienylor benzyl, where the substituted methyl, ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl,2-propyn-1-yl, 3-methyl-3-buten-1-yl, and -methylcyclohexyl issubstituted by one or more substituents independently selected fromhalo, alkoxy, aryloxy, alkylthio and arylthio; the subsituted thienyl issubstituted by one or more substituents independently selected fromlower alkyl, lower alkoxy, hydroxy, amino, alkylamino, dialkylamino andhalo; and the phenyl moiety of the substituted benzyl is substituted byone or more substituents independently selected from lower alkyl, loweralkoxy, alkylenedioxy, hydroxy, amino, alkylamino, dialkylamino andhalo; more preferably, R^(x) is H and R^(y) is ethyl, n-propyl,iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl,2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, benzyl orsubstituted benzyl, wherein the phenyl moiety of the substituted benzylcomprises one or more substituents independently selected from C₁-C₄alkyl, C₁-C₄ alkoxy and halo; even more preferably, where R^(x) is H andR^(y) is H, ethyl, 2-propyn-1-yl, methylcyclohexyl or benzyl;

[0224] R^(c) is

[0225] where n is 1 or 2; preferably R^(c) is

[0226] where n is 1; more preferably, R^(c) is

[0227] and

[0228] R^(b), R^(d), Z and Z¹ are defined as in Formula I, above.

[0229] Yet other specific compounds of this invention have the formula:

[0230] wherein:

[0231] R^(a′) is a (C₁-C₄)alkyl, (C₃-C₈)cycloalkyl, aryl or heteroarylgroup, wherein the (C₁-C₄)alkyl, (C₃-C₈)cycloalkyl, aryl and heteroarylgroup is unsubstituted or substituted with one or more suitablesubstituents provided that R^(a′) is not an amino-substituted(C₁-C₄)alkyl group; preferably, R^(a′) is a (C₁-C₄)alkyl, phenyl,naphthyl, pyrrolyl or indolyl group, where the (C₁-C₄)alkyl group isunsubstituted or substituted with one or more substituents independentlyselected from halo, C₁-C₄ alkoxy or C₁-C₄ haloalkoxy and the phenyl,naphthyl, pyrrolyl or indolyl group is unsubstituted or substituted withone or more substituents independently selected from halo, C₁-C₄ alkyl,C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, methylenedioxy, aryl,heterocycloalkyl, and heteroaryl, where the aryl, heterocycloalkyl orheteroaryl is unsubstituted or substituted by one ore more substituentsindependently selected from halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, C₁-C₄ haloalkoxy and methylenedioxy; more preferably, R^(a′) isa pyrrolyl or indolyl group, where the pyrrolyl or indolyl group isunsubstituted or substituted by one or more substituents independentlyselected from halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl or a phenyl, naphthyl,isoxazolyl, pyridyl, quinoyl or isoquinoyl group, where the phenyl,naphthyl, isoxazolyl, pyridyl, quinoyl or isoquinoyl group isunsubstituted or substituted with one or more substituents independentlyselected from halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄haloalkoxy and methylenedioxy; even more preferably, R^(a′) is apyrrolyl group that is unsubstituted or substituted by phenyl,α-naphthyl, β-naphthyl, 2-chlorophenyl, 2-α,α,α-trifluoromethylphenyl,3-chloro-6-methoxyphenyl, 2,3-dichlorophenyl, 4-isoquinoyl,3-iso-propylphenyl, 2,5-dimethoxyphenyl, 2-methoxyphenyl, 2-methylphenyl(o-tolyl), 2-bromophenyl, 3-pyridyl, 4-pyridyl, 3-methyl-isoxazol-5-yl,3,3,3-trifluoroprop-1-yl, or 2,3-benzo[d]dioxolyl;

[0232] n is 1, 2 or 3; preferably n is 1;

[0233] R^(x) is H and R^(y) is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl or anarylalkyl, heteroarylalkyl, cycloalkylalkyl group or a straight-chainsaturated hydrocarbon moiety or an unsaturated hydrocarbon moiety, wherethe arylalkyl, heteroarylalkyl, cycloalkylalkyl group is unsubstitutedor substituted with one or more suitable substituents; preferably, R^(x)is H and R^(y) is substituted or unsubstituted methyl, ethyl, n-propyl,iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl,2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, -methylthienylor benzyl, where the substituted methyl, ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl,2-propyn-1-yl, 3-methyl-3-buten-1-yl, and -methylcyclohexyl issubstituted by one or more substituents independently selected fromhalo, alkoxy, aryloxy, alkylthio and arylthio; the subsituted thienyl issubstituted by one or more substituents independently selected fromlower alkyl, lower alkoxy, hydroxy, amino, alkylamino, dialkylamino andhalo; and the phenyl moiety of the substituted benzyl is substituted byone or more substituents independently selected from lower alkyl, loweralkoxy, alkylenedioxy, hydroxy, amino, alkylamino, dialkylamino andhalo; more preferably, R^(x) is H and R^(y) is ethyl, n-propyl,iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl,2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, benzyl orsubstituted benzyl, wherein the phenyl moiety of the substituted benzylcomprises one or more substituents independently selected from C₁-C₄alkyl, C₁-C₄ alkoxy and halo; even more preferably, where R^(x) is H andR^(y) is H, ethyl, 2-propyn-1-yl, methylcyclohexyl or benzyl;

[0234] R^(c) is

[0235] where n is 1 or 2; preferably R^(c) is

[0236] where n is 1; more preferably, R^(c) is

[0237] and

[0238] R^(b), R^(d), Z and Z¹ are defined as in Formula I, above.

[0239] Another embodiment of this invention comprises compounds havingthe formula:

[0240] wherein:

[0241] R^(a′) is a (C₁-C₄)alkyl, (C₃-C₈)cycloalkyl, heterocycloalkyl,aryl or heteroaryl group, wherein the (C₁-C₄)alkyl, (C₃-C₈)cycloalkyl,heterocycloalkyl, aryl and heteroaryl group is unsubstituted orsubstituted with one or more suitable substituents; preferably, R^(a′)is a (C₁-C₄)alkyl, phenyl or naphthyl group, where the (C₁-C₄)alkylgroup is unsubstituted or substituted with one or more substituentsindependently selected from halo, C₁-C₄ alkoxy or C₁-C₄ haloalkoxy andthe phenyl or naphthyl group is unsubstituted or substituted with one ormore substituents independently selected from halo, C₁-C₄ alkyl, C₁-C₄haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, methylenedioxy and phenyl,where the phenyl is unsubstituted or substituted by one or moresubstituents independently selected from halo, C₁-C₄ alkyl, C₁-C₄haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy and methylenedioxy; inspecific embodiments, R^(a′) is a halo-substituted phenyl group;

[0242] n is 1, 2 or 3; preferably, n is 1 or 2; more preferably, n is 1;

[0243] R^(x) is H and R^(y) is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl or anarylalkyl, heteroarylalkyl, cycloalkylalkyl group or a straight-chainsaturated hydrocarbon moiety or an unsaturated hydrocarbon moiety, wherethe arylalkyl, heteroarylalkyl, cycloalkylalkyl group is unsubstitutedor substituted with one or more suitable substituents; preferably, R^(x)is H and R^(y) is substituted or unsubstituted methyl, ethyl, n-propyl,iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl,2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, -methylthienylor benzyl, where the substituted methyl, ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl,2-propyn-1-yl, 3-methyl-3-buten-1-yl, and -methylcyclohexyl issubstituted by one or more substituents independently selected fromhalo, alkoxy, aryloxy, alkylthio and arylthio; the subsituted thienyl issubstituted by one or more substituents independently selected fromlower alkyl, lower alkoxy, hydroxy, amino, alkylamino, dialkylamino andhalo; and the phenyl moiety of the substituted benzyl is substituted byone or more substituents independently selected from lower alkyl, loweralkoxy, alkylenedioxy, hydroxy, amino, alkylamino, dialkylamino andhalo; more preferably, R^(x) is H and R^(y) is ethyl, n-propyl,iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl,2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, benzyl orsubstituted benzyl, wherein the phenyl moiety of the substituted benzylcomprises one or more substituents independently selected from C₁-C₄alkyl, C₁-C₄ alkoxy and halo; even more preferably, where R^(x) is H andR^(y) is H, ethyl, 2-propyn-1-yl, methylcyclohexyl or benzyl; and

[0244] and R^(b), R^(c), R^(d), Z and Z¹ are defined as in Formula I,above.

[0245] Other specific embodiments of this invention comprise thecompounds having the formula:

[0246] wherein:

[0247] W is CH or N;

[0248] R^(a′) is a C₁-C₄ alkyl, C₃-C₈ cycloalkyl, aryl or heteroarylgroup, where the C₁-C₄ alkyl, C₃-C₈ cycloalkyl, aryl, and heteroarylgroup is unsubstituted or substituted with one or more suitablesubstituents, provided that R^(a′) is not an amino-substituted alkylgroup; preferably, R^(a′) is a C₁-C₄ alkyl, C₅-C₆ cycloalkyl, phenyl,naphthyl or heteroaryl group, where the phenyl, naphthyl or heteroarylgroup is unsubstituted or substituted with one or more substituentsindependently selected from halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, C₁-C₄ haloalkoxy, methylenedioxy, aryl, heterocycloalkyl, andheteroaryl, where the aryl, heterocycloalkyl and heteroaryl isunsubstituted or substituted by one ore more substituents independentlyselected from halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄haloalkoxy and methylenedioxy; more preferably, R^(a′) is a C₁-C₄ alkyl,C₅-C₆ cycloalkyl, phenyl, naphthyl, pyrrolyl or indolyl, group, wherethe phenyl, naphthyl, pyrrolyl or indolyl, group is unsubstituted orsubstituted with one .or more substituents independently selected fromhalo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy,methylenedioxy and a phenyl, naphthyl, isoquinoyl, pyridyl or isoxazolylgroup, wherein the phenyl, naphthyl, isoquinoyl, pyridyl and isoxazolylgroup is unsubstituted or substituted by one ore more substituentsindependently selected from halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, C₁-C₄ haloalkoxy and methylenedioxy;

[0249] R⁴ and R⁶ are each independently H or C₁-C₄ alkyl; preferably R⁴and R⁶ are each H;

[0250] R⁵ is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl or an arylalkyl,heteroarylalkyl, cycloalkylalkyl group or a straight-chain saturatedhydrocarbon moiety or an unsaturated hydrocarbon moiety, where thearylalkyl, heteroarylalkyl, cycloalkylalkyl group is unsubstituted orsubstituted with one or more suitable substituents; preferably, R⁵ is Hor substituted or unsubstituted methyl, ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl,2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, -methylthienylor benzyl, where the substituted methyl, ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl,2-propyn-1-yl, 3-methyl-3-buten-1-yl, and -methylcyclohexyl issubstituted by one or more substituents independently selected fromhalo, alkoxy, aryloxy, alkylthio and arylthio; the subsituted thienyl issubstituted by one or more substituents independently selected fromlower alkyl, lower alkoxy, hydroxy, amino, alkylamino, dialkylamino andhalo; and the phenyl moiety of the substituted benzyl is substituted byone or more substituents independently selected from lower alkyl, loweralkoxy, alkylenedioxy, hydroxy, amino, alkylamino, dialkylamino andhalo; more preferably, R⁵ is H, ethyl, n-propyl, iso-propyl, n-butyl,sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl,3-methyl-3-buten-1-yl, -methylcyclohexyl, benzyl or substituted benzyl,wherein the phenyl moiety of the substituted benzyl comprises one ormore substituents independently selected from C₁-C₄ alkyl, C₁-C₄ alkoxyand halo; even more preferably, R⁵ is H, ethyl, 2-propyn-1-yl,methylcyclohexyl or benzyl;

[0251] R⁷ is

[0252] where n is 1 or 2; preferably, R⁷ is

[0253] where n is 1; most preferably, R⁷ is

[0254] and

[0255] Z¹ is H or C₁-C₄ alkyl and Z is —CO₂-alkyl, —CO₂-cycloalkyl,—CO₂-alkylaryl or —CO₂-alkylheterocycloaryl, or Z¹ and Z taken togetherwith the atom to which they are attached form

[0256] preferably, Z¹ is H and Z is —CO₂CH₂CH₃, —CO₂(CH(CH₃)₂),—CO₂(C(CH₃)₃), —CO₂CH₂(C(CH₃)₃), —CO₂(cyclo-C₅H₉) or Z¹ and Z takentogether with the atom to which they are attached form

[0257] most preferably, Z¹ is H and Z is —CO₂CH₂CH₃ or Z¹ and Z takentogether with the atom to which they are attached form

[0258] or a prodrug, pharmaceutically acceptable salt, pharmaceuticallyactive metabolite, or pharmaceutically acceptable solvate of saidcompound.

[0259] Specific embodiments of Formula VI of this invention comprise thecompounds depicted by the formula:

[0260] and the compounds depicted by the formula:

[0261] wherein R^(a′), R⁴, R⁵, R⁶, R⁷, Z and Z¹ are as defined above.

[0262] In addition, specific embodiments of this invention comprise thecompounds depicted by the formula:

[0263] wherein:

[0264] R¹ is H, halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or an aryl orheteroaryl group, where the aryl or heteroaryl group is unsubstituted orsubstituted with one or more suitable substituents; preferably, R¹ is H,halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl or a phenyl, naphthyl, isoxazolyl,pyridyl, quinoyl or isoquinoyl group, where the phenyl, naphthyl,isoxazolyl, pyridyl, quinoyl or isoquinoyl group is unsubstituted orsubstituted with one or more substituents independently selected from:halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy andmethylenedioxy; more preferably, R¹ is H, phenyl, α-naphthyl,β-naphthyl, 2-chlorophenyl, 2-α,α,α-trifluoromethylphenyl,3-chloro-6-methoxyphenyl, 2,3-dichlorophenyl, 4-isoquinoyl,3-iso-propylphenyl, 2,5-dimethoxyphenyl, 2-methoxyphenyl, 2-methylphenyl(o-tolyl), 2-bromophenyl, 3-pyridyl, 4-pyridyl, 3-methyl-isoxazol-5-yl,3,3,3-trifluoroprop-1-yl, or 2,3-benzo[d]dioxolyl;

[0265] R² and R³ are each independently H or C₁-C₄ alkyl; preferably R²and R³ are each H; or

[0266] R¹ together with R² form a cycloalkyl, heterocycloalkyl, aryl orheteroaryl ring, where the cycloalkyl, heterocycloalkyl, aryl orheteroaryl ring is unsubstituted or substituted with one or moresuitable substituents; or preferably, R¹ together with R² form a phenylring, which is unsubstituted or substituted with one or more suitablesubstituents and R³ is H;

[0267] R⁴ and R⁶ are each independently H or C₁-C₄ alkyl; preferably R⁴and R⁶ are each H;

[0268] R⁵ is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl or an arylalkyl,heteroarylalkyl, cycloalkylalkyl group or a straight-chain saturatedhydrocarbon moiety or an unsaturated hydrocarbon moiety, where thearylalkyl, heteroarylalkyl, cycloalkylalkyl group is unsubstituted orsubstituted with one or more suitable substituents; preferably, R⁵ is Hor substituted or unsubstituted methyl, ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl,2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, -methylthienylor benzyl, where the substituted methyl, ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl,2-propyn-1-yl, 3-methyl-3-buten-1-yl, and -methylcyclohexyl issubstituted by one or more substituents independently selected fromhalo, alkoxy, aryloxy, alkylthio and arylthio; the subsituted thienyl issubstituted by one or more substituents independently selected fromlower alkyl, lower alkoxy, hydroxy, amino, alkylamino, dialkylamino andhalo; and the phenyl moiety of the substituted benzyl is substituted byone or more substituents independently selected from lower alkyl, loweralkoxy, alkylenedioxy, hydroxy, amino, alkylamino, dialkylamino andhalo; more preferably, R⁵ is H, ethyl, n-propyl, iso-propyl, n-butyl,sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl,3-methyl-3-buten-1-yl, -methylcyclohexyl, benzyl or substituted benzyl,wherein the phenyl moiety of the substituted benzyl comprises one ormore substituents independently selected from C₁-C₄ alkyl, C₁-C₄ alkoxyand halo; even more preferably, R⁵ is H, ethyl, 2-propyn-1-yl,methylcyclohexyl or benzyl;

[0269] R⁷ is selected from —CH₂CH₂C(O)NH₂; —CH₂CH₂C(O)NH-alkyl;—CH₂NHC(O)CH₃; and

[0270] where n is 1 or 2; preferably, R⁷ is —CH₂CH₂C(O)NH₂ or

[0271] where n is 1; most preferably, R⁷ is —CH₂CH₂C(O)NH₂ or

[0272] and

[0273] Z¹ is H or C₁-C₄ alkyl and Z is —CO₂-alkyl, —CO₂-cycloalkyl,—CO₂-alkylaryl or —CO₂-alkylheterocycloaryl, or Z¹ and Z taken togetherwith the atom to which they are attached form

[0274] preferably, Z¹ is H and Z is —CO₂CH₂CH₃, —CO₂(CH(CH₃)₂),—CO₂(C(CH₃)₃), —CO₂CH₂(C(CH₃)₃), —CO₂(cyclo-C₅H₉) or Z¹ and Z takentogether with the atom to which they are attached form

[0275] most preferably, Z¹ is H and Z is —CO₂CH₂CH₃ or Z¹ and Z takentogether with the atom to which they are attached form

[0276] or a prodrug, pharmaceutically acceptable salt, pharmaceuticallyactive metabolite, or pharmaceutically acceptable solvate of saidcompound.

[0277] Another specific embodiment of this invention comprises thecompounds depicted by the formula:

[0278] wherein:

[0279] R¹ is H, halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or an aryl orheteroaryl group, where the aryl or heteroaryl group is unsubstituted orsubstituted with one or more suitable substituents; preferably, R¹ is H,halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl or a phenyl, naphthyl, isoxazolyl,pyridyl, quinoyl or isoquinoyl group, where the phenyl, naphthyl,isoxazolyl, pyridyl, quinoyl or isoquinoyl group is unsubstituted orsubstituted with one or more substituents independently selected from:halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy andmethylenedioxy; more preferably, R¹ is H, phenyl, α-naphthyl,β-naphthyl, 2-chlorophenyl, 2-α,α,α-trifluoromethylphenyl,3-chloro-6-methoxyphenyl, 2,3-dichlorophenyl, 4-isoquinoyl,3-iso-propylphenyl, 2,5-dimethoxyphenyl, 2-methoxyphenyl, 2-methylphenyl(o-tolyl), 2-bromophenyl, 3-pyridyl, 4-pyridyl, 3-methyl-isoxazol-5-yl,3,3,3-trifluoroprop-1-yl, or 2,3-benzo[d]dioxolyl;

[0280] R² and R³ are each independently H or C₁-C₄ alkyl; preferably R²and R³ are each H; or

[0281] R¹ together with R² form a cycloalkyl, heterocycloalkyl, aryl orheteroaryl ring, where the cycloalkyl, heterocycloalkyl, aryl orheteroaryl ring is unsubstituted or substituted with one or moresuitable substituents; or preferably, R¹ together with R² form anunsubstituted phenyl ring and R³ is H;

[0282] R⁴ and R⁶ are each independently H or C₁-C₄ alkyl; preferably R⁴and R⁶ are each H;

[0283] R⁵ is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl or an arylalkyl,heteroarylalkyl, cycloalkylalkyl group or a straight-chain saturatedhydrocarbon moiety or an unsaturated hydrocarbon moiety, where thearylalkyl, heteroarylalkyl, cycloalkylalkyl group is unsubstituted orsubstituted with one or more suitable substituents; preferably, R⁵ is Hor substituted or unsubstituted methyl, ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl,2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, -methylthienylor benzyl, where the substituted methyl, ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl,2-propyn-1-yl, 3-methyl-3-buten-1-yl, and -methylcyclohexyl issubstituted by one or more substituents independently selected fromhalo, alkoxy, aryloxy, alkylthio and arylthio; the subsituted thienyl issubstituted by one or more substituents independently selected fromlower alkyl, lower alkoxy, hydroxy, amino, alkylamino, dialkylamino andhalo; and the phenyl moiety of the substituted benzyl is substituted byone or more substituents independently selected from lower alkyl, loweralkoxy, alkylenedioxy, hydroxy, amino, alkylamino, dialkylamino andhalo; more preferably, R⁵ is H, ethyl, n-propyl, iso-propyl, n-butyl,sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl,3-methyl-3-buten-1-yl, -methylcyclohexyl, benzyl or substituted benzyl,wherein the phenyl moiety of the substituted benzyl comprises one ormore substituents independently selected from C₁-C₄ alkyl, C₁-C₄ alkoxyand halo; even more preferably, R⁵ is H, ethyl, 2-propyn-1-yl,methylcyclohexyl or benzyl;

[0284] R⁷ is selected from —CH₂CH₂C(O)NH₂; —CH₂CH₂C(O)NH-alkyl;—CH₂NHC(O)CH₃; and

[0285] where n is 1 or 2; preferably, R⁷ is —CH₂CH₂C(O)NH₂ or

[0286] where n is 1; most preferably, R⁷ is —CH₂CH₂C(O)NH₂ or

[0287] provided that when R¹ together with R² form a phenyl ring and thephenyl ring is substituted, R⁷ is selected from

[0288] where n is 1 or 2,

[0289] where n is 1, or

[0290] and

[0291] Z¹ is H or C₁-C₄ alkyl and Z is —CO₂-alkyl, —CO₂-cycloalkyl,—CO₂-alkylaryl or —CO₂-alkylheterocycloaryl, or Z¹ and Z taken togetherwith the atom to which they are attached form

[0292] preferably, Z¹ is H and Z is —CO₂CH₂CH₃, —CO₂(CH(CH₃)₂),—CO₂(C(CH₃)₃), —CO₂CH₂(C(CH₃)₃), —CO₂(cyclo-C₅H₉) or Z¹ and Z takentogether with the atom to which they are attached form

[0293] most preferably, Z¹ is H and Z is —CO₂CH₂CH₃ or Z¹ and Z takentogether with the atom to which they are attached form

[0294] or a prodrug, pharmaceutically acceptable salt, pharmaceuticallyactive metabolite, or pharmaceutically acceptable solvate of saidcompound.

[0295] Yet another specific embodiment of this invention comprises thecompounds depicted by the formula:

[0296] wherein:

[0297] each R^(z) is independently selected from halo and a C₁-C₄alkoxy, C₁-C₄ alkyl, aryl, heterocycloalkyl or heteroaryl group wherethe C₁-C₄ alkoxy or C₁-C₄ alkyl group is unsubstituted or substitutedwith one or more substituents independently selected from halo, C₁-C₄alkoxy or C₁-C₄ haloalkoxy and the aryl, heterocycloalkyl or heteroarylgroup is unsubstituted or substituted by one ore more substituentsindependently selected from halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, C₁-C₄ haloalkoxy and methylenedioxy and n_(z) is an integer from1 to 4; preferably, each R^(z) is independently selected from halo,C₁-C₄ alkoxy, unsubstituted C₁-C₄ alkyl, C₁-C₄ haloalkyl, and C₁-C₄alkoxyalkyl and n_(z) is an integer from 1 to 2; more preferably, eachR^(z) is independently selected from halo, C₁-C₄ alkoxy, unsubstitutedC₁-C₄ alkyl and C₁-C₄ haloalkyl, and n_(z) is 1 or 2;

[0298] R³ is H, halo, C₁-C₄ alkoxy, unsubstituted C₁-C₄ alkyl, C₁-C₄haloalkyl and C₁-C₄ alkoxyalkyl; preferably, R³ is H or C₁-C₄ alkyl;more preferably, R³ is H;

[0299] R⁴ and each R⁶ are independently selected from H, unsubstitutedlower alkyl, haloalkyl and lower alkoxyalkyl, preferably, R⁴ and each R⁶are independently H or C₁-C₄ alkyl; more preferably R⁴ and R⁶ are eachH;

[0300] R⁵ is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl or an arylalkyl,heteroarylalkyl, cycloalkylalkyl group or a straight-chain saturatedhydrocarbon moiety or an unsaturated hydrocarbon moiety, where thearylalkyl, heteroarylalkyl, cycloalkylalkyl group is unsubstituted orsubstituted with one or more suitable substituents; preferably, R⁵ is Hor substituted or unsubstituted methyl, ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl,2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, -methylthienylor benzyl, where the substituted methyl, ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl,2-propyn-1-yl, 3-methyl-3-buten-1-yl, and -methylcyclohexyl issubstituted by one or more substituents independently selected fromhalo, alkoxy, aryloxy, alkylthio and arylthio; the subsituted thienyl issubstituted by one or more substituents independently selected fromlower alkyl, lower alkoxy, hydroxy, amino, alkylamino, dialkylamino andhalo; and the phenyl moiety of the substituted benzyl is substituted byone or more substituents independently selected from lower alkyl, loweralkoxy, alkylenedioxy, hydroxy, amino, alkylamino, dialkylamino andhalo; more preferably, R⁵ is H, ethyl, n-propyl, iso-propyl, n-butyl,sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl,3-methyl-3-buten-1-yl, -methylcyclohexyl, benzyl or substituted benzyl,wherein the phenyl moiety of the substituted benzyl comprises one ormore substituents independently selected from C₁-C₄ alkyl, C₁-C₄ alkoxyand halo; even more preferably, R⁵ is H, ethyl, 2-propyn-1-yl,methylcyclohexyl or benzyl;

[0301] R⁷ is

[0302] where n is 1 or 2; preferably, R⁷ is

[0303] where n is 1; most preferably, R⁷ is

[0304] and

[0305] Z¹ is H or C₁-C₄ alkyl and Z is —CO₂-alkyl, —CO₂-cycloalkyl,—CO₂-alkylaryl or —CO₂-alkylheterocycloaryl, or Z¹ and Z taken togetherwith the atom to which they are attached form

[0306] preferably, Z¹ is H and Z is —CO₂CH₂CH₃, —CO₂(CH(CH₃)₂),—CO₂(C(CH₃)₃), —CO₂CH₂(C(CH₃)₃), —CO₂(cyclo-C₅H₉) or Z¹ and Z takentogether with the atom to which they are attached form

[0307] most preferably, Z¹ is H and Z is —CO₂CH₂CH₃ or Z¹ and Z takentogether with the atom to which they are attached form

[0308] or a prodrug, pharmaceutically acceptable salt, pharmaceuticallyactive metabolite, or pharmaceutically acceptable solvate of saidcompound.

[0309] Another preferred embodiment of this invention comprises thecompounds of Formula XII, depicted by the formula:

[0310] wherein:

[0311] R^(a′) is a C₁-C₄ alkyl, aryl, C₃-C₇ cycloalkyl, heterocycloalkylor heteroaryl group, where the C₁-C₄ alkyl, aryl, C₃-C₇ cycloalkyl,heterocycloalkyl or heteroaryl group is unsubstituted or substitutedwith one or more substituents independently selected from alkyl,haloalkyl, alkylenedioxy (as a substituent for aryl or heteroaryl),nitro, amino, hydroxamino, alkylamino, dialkylamino, halo, hydroxyl,alkoxy, haloalkoxy, aryloxy, mercapto, alkylthio or arylthio, aryl orheteroaryl, where the aryl or heteroaryl group is unsubstituted orsubstituted with one or more substituents independently selected fromhalo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy andmethylenedioxy; preferably, R^(a′) is a C₁-C₄ alkyl, C₁-C₄ haloalkyl,phenyl, naphthyl, C₅-C₆ cycloalkyl, isoquinoyl, pyridyl or pyrrolylgroup, where the phenyl, naphthyl, isoquinoyl, pyridyl or pyrrolyl groupis unsubstituted or substituted with one or more substituentsindependently selected from halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, C₁-C₄ haloalkoxy and methylenedioxy; more preferably, R^(a′) isa phenyl group, where the phenyl group is unsubstituted or substitutedwith one or more substituents independently selected from halo, C₁-C₄alkyl, C₁-C₄ haloalkyl or C₁-C₄ alkoxy;

[0312] each R⁶ is independently H or C₁-C₄ alkyl; preferably, each R⁶ isH;

[0313] R⁵ is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl or an arylalkyl,heteroarylalkyl, cycloalkylalkyl group or a straight-chain saturatedhydrocarbon moiety or an unsaturated hydrocarbon moiety, where thearylalkyl, heteroarylalkyl, cycloalkylalkyl group is unsubstituted orsubstituted with one or more suitable substituents; preferably, R⁵ is Hor substituted or unsubstituted methyl, ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl,2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, -methylthienylor benzyl, where the substituted methyl, ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl,2-propyn-1-yl, 3-methyl-3-buten-1-yl, and -methylcyclohexyl issubstituted by one or more substituents independently selected fromhalo, alkoxy, aryloxy, alkylthio and arylthio; the subsituted thienyl issubstituted by one or more substituents independently selected fromlower alkyl, lower alkoxy, hydroxy, amino, alkylamino, dialkylamino andhalo; and the phenyl moiety of the substituted benzyl is substituted byone or more substituents independently selected from lower alkyl, loweralkoxy, alkylenedioxy, hydroxy, amino, alkylamino, dialkylamino andhalo; more preferably, R⁵ is H, ethyl, n-propyl, iso-propyl, n-butyl,sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl,3-methyl-3-buten-1-yl, -methylcyclohexyl, benzyl or substituted benzyl,wherein the phenyl moiety of the substituted benzyl comprises one ormore substituents independently selected from C₁-C₄ alkyl, C₁-C₄ alkoxyand halo; even more preferably, R⁵ is H, ethyl, 2-propyn-1-yl,methylcyclohexyl or benzyl;

[0314] R⁷ is selected from —CH₂CH₂C(O)NH₂; —CH₂CH₂C(O)NH-alkyl;—CH₂NHC(O)CH₃; and

[0315] where n is 1 or 2; preferably, R⁷ is —CH₂CH₂C(O)NH₂ or

[0316] where n is 1; most preferably, R⁷ is —CH₂CH₂C(O)NH₂ or

[0317] and

[0318] Z¹ is H or C₁-C₄ alkyl and Z is —CO₂-alkyl, —CO₂-cycloalkyl,—CO₂-alkylaryl or —CO₂-alkylheterocycloaryl, or Z¹ and Z taken togetherwith the atom to which they are attached form

[0319] preferably, Z¹ is H and Z is —CO₂CH₂CH₃, —CO₂(CH(CH₃)₂),—CO₂(C(CH₃)₃), —CO₂CH₂(C(CH₃)₃), —CO₂(cyclo-C₅H₉) or Z¹ and Z takentogether with the atom to which they are attached form

[0320] most preferably, Z¹ is H and Z is —CO₂CH₂CH₃ or Z¹ and Z takentogether with the atom to which they are attached form

[0321] or a prodrug, pharmaceutically acceptable salt, pharmaceuticallyactive metabolite, or pharmaceutically acceptable solvate of saidcompound.

[0322] Preferred embodiments of this invention comprise the compoundsdepicted by the formula:

[0323] wherein R^(a′) is an alkyl, cycloalkyl, aryl or heteroaryl group,where said alkyl, cycloalkyl, aryl, and heteroaryl group isunsubstituted or substituted with one or more suitable substituents, andeach W, R⁴, R⁵, R⁶, R⁷, Z and Z¹ are as defined in VI above, providedthat R^(a′) is not amino-substituted alkyl.

[0324] Particularly preferred embodiments of the compounds of FormulaVI-a comprise the compounds depicted by the formula:

[0325] wherein R^(a′) is an alkyl, cycloalkyl, aryl or heteroaryl group,where said alkyl, cycloalkyl, aryl, and heteroaryl group isunsubstituted or substituted with one or more suitable substituents, andeach R⁴, R⁵, R⁶, R⁷, Z and Z¹ are as defined above, provided that R^(a′)is not amino-substituted alkyl.

[0326] Other preferred embodiments of the compounds of Formula VI-acomprise the compounds depicted by the formula:

[0327] wherein R^(a′) is an alkyl, cycloalkyl, aryl or heteroaryl group,where said alkyl, cycloalkyl, aryl, and heteroaryl group isunsubstituted or substituted with one or more suitable substituents, andeach R⁴, R⁵, R⁶, R⁷, Z and Z¹ are as defined above, provided that R^(a′)is not amino-substituted alkyl.

[0328] More preferably, the compounds of this invention have theformula:

[0329] wherein R¹ is an alkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl group, where the alkyl, cycloalkyl, heterocycloalkyl, aryl,and heteroaryl group is unsubstituted or substituted with one or moresuitable substituents, and each R², R³, R⁴, R⁵, R⁶, R⁷, Z and Z¹ are asdefined above for IX.

[0330] In another preferred embodiment, the compounds of this inventionhave the formula:

[0331] wherein each R¹, R², R³, R⁴, R⁵, R⁶, R⁷, Z and Z¹ are as definedabove.

[0332] Yet another preferred embodiment of this invention comprises thecompounds depicted by the formula:

[0333] wherein each R^(z), R³, R⁴, R⁵, R⁶, Z and Z¹ are as defined aboveand R⁷ is a moiety having the formula:

[0334] wherein each R⁸, R⁹, A₁, A₂, A₃, A₄ and p are as defined above.

[0335] Another particularly preferred embodiment of this inventioncomprises the compounds depicted by the formula:

[0336] wherein each R^(a′), R⁵, R⁶, R⁷, Z and Z¹ are as defined above.More preferably, R⁵ is H and the invention comprises the compoundsdepicted by the formula:

[0337] wherein each R^(a′), R⁶, R⁷, Z and Z¹ are as defined above.

[0338] In the compounds of Formulas VI-a to XII-b, R⁶ is preferably H.In the compounds of Formulas VI-a to XI-a, each R⁴ and R⁶ is preferablyH.

[0339] Preferred specific compounds include those of any of the Examplesbelow, especially:

[0340] Preferred specific embodiments of the compounds of this inventioninclude any one of the following:

[0341] The invention is also directed to intermediate compounds ofFormula XIII which are useful in the synthesis of certain compounds ofFormulas I-XII:

[0342] wherein R^(5′) is a lower alkyl or aryl group, where the loweralkyl or aryl group is unsubstituted or substituted with one or moresuitable substituents, (where —CH₂—R⁵′ represents R⁵ as defined above)and R^(E) is H or an alkyl or aryl group, where the alkyl or aryl groupis unsubstituted or substituted with one or more suitable substituents.

[0343] The invention is also directed to pharmaceutically acceptablesalts of the compounds of Formulas XIII. Preferred examples of thecompounds of Formula XIII, include the following:

[0344] and pharmaceutically acceptable salts thereof. Exemplarypreferred R^(E) groups include, but are not limited to, H, methyl,tert-butyl, allyl, and benzyl, as illustrated in the following:

[0345] The antipicornaviral compounds of this invention includeprodrugs, the pharmaceutically active metabolites, and thepharmaceutically acceptable salts and solvates thereof. In preferredembodiments, the compounds of Formulas I to XII, prodrugs,pharmaceutically acceptable salts, and pharmaceutically activemetabolites and solvates thereof have an antipicornaviral activity, morepreferably antirhinoviral activity, corresponding to an EC₅₀ less thanor equal to 100 μM in the H1-HeLa cell culture assay.

[0346] A “prodrug” is intended to mean a compound that is convertedunder physiological conditions or by solvolysis or metabolically to aspecified compound that is pharmaceutically active. A prodrug may be aderivative of one of the compounds of this invention that contains amoiety, such as for example —CO₂R, —PO(OR)₂ or —C═NR, that may becleaved under physiological conditions or by solvolysis. Any suitable Rsubstituent may be used that provides a pharmaceutically acceptablesolvolysis or cleavage product. A prodrug containing such a moiety maybe prepared according to conventional procedures by treatment of acompound of this invention containing, for example, an amido, carboxylicacid, or hydroxyl moiety with a suitable reagent. A “pharmaceuticallyactive metabolite” is intended to mean a pharmacologically activecompound produced through metabolism in the body of a specifiedcompound. Prodrugs and active metabolites of compounds of this inventionof the above-described Formulas may be determined using techniques knownin the art, for example, through metabolic studies. See, e.g., “Designof Prodrugs,” (Bundgaard, ed.), 1985, Elsevier Publishers B.V.,Amsterdam, The Netherlands. A “pharmaceutically acceptable salt” isintended to mean a salt that retains the biological effectiveness of thefree acids and bases of a specified compound and that is notbiologically or otherwise undesirable. Examples of pharmaceuticallyacceptable salts include sulfates, pyrosulfates, bisulfates, sulfites,bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates,metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates,propionates, decanoates, caprylates, acrylates, formates, isobutyrates,caproates, heptanoates, propiolates, oxalates, malonates, succinates,suberates, sebacates, fumarates, maleates, butyne-1,4-dioates,hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates,sulfonates, xylenesulfonates, phenylacetates, phenylpropionates,phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycollates,tartrates, methane-sulfonates (mesylates), propanesulfonates,naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates. A“solvate” is intended to mean a pharmaceutically acceptable solvate formof a specified compound that retains the biological effectiveness ofsuch compound. Examples of solvates include compounds of the inventionin combination with water, isopropanol, ethanol, methanol, DMSO, ethylacetate, acetic acid, or ethanolamine. In the case of compounds, salts,or solvates that are solids, it is understood by those skilled in theart that the inventive compounds, salts, and solvates may exist indifferent crystal forms, all of which are intended to be within thescope of the present invention and specified formulas.

[0347] The present invention is also directed to a method of inhibitingpicornaviral 3C protease activity, comprising contacting the proteasewith an effective amount of a compound of Formulas I to XII, or apharmaceutically acceptable salt, prodrug, pharmaceutically activemetabolite, or solvate thereof. For example, picornaviral 3C proteaseactivity may be inhibited in mammalian tissue by administering acompound of Formulas I to XII or a pharmaceutically acceptable salt,prodrug, pharmaceutically active metabolite, or solvate thereof. Morepreferably, the present method is directed at inhibiting rhinoviralprotease activity. “Treating” or “treatment” is intended to mean atleast the mitigation of a disease condition in a mammal, such as ahuman, that is alleviated by the inhibition of the activity of one ormore picornaviral 3C proteases, including, but not limited to humanrhinoviruses, human poliovirus, human coxsackieviruses,encephalomyocarditis viruses, meningitis virus, and hepatitis A virus.The methods of treatment for mitigation of a disease condition includethe use of the compounds in this invention in any conventionallyacceptable manner, for example, as a prophylactic. The activity of theinventive compounds as inhibitors of picornaviral 3C protease activitymay be measured by any of the suitable methods known to those skilled inthe art, including in vivo and in vitro assays. An example of a suitableassay for activity measurements is the antiviral H1-HeLa cell cultureassay described herein.

[0348] Administration of the compounds of the Formulas I to XII andtheir pharmaceutically acceptable prodrugs, salts, active metabolites,and solvates may be performed according to any of the generally acceptedmodes of administration available to those skilled in the art.Illustrative examples of suitable modes of administration include oral,nasal, parenteral, topical, transdermal, and rectal.

[0349] An inventive compound of Formulas I to XII or a pharmaceuticallyacceptable salt, prodrug, active metabolite, or solvate thereof may beadministered as a pharmaceutical composition in any pharmaceutical formrecognizable to the skilled artisan as being suitable. Suitablepharmaceutical forms include solid, semisolid, liquid, or lyophilizedformulations, such as tablets, powders, capsules, suppositories,suspensions, liposomes, and aerosols. Pharmaceutical compositions of theinvention may also include suitable excipients, diluents, vehicles, andcarriers, as well as other pharmaceutically active agents, dependingupon the intended use or mode of administration. In preferredembodiments, the inventive pharmaceutical compositions are deliveredorally, or intranasally in the form of suspensions. Acceptable methodsof preparing suitable pharmaceutical forms of the pharmaceuticalcompositions may be routinely determined by those skilled in the art.For example, pharmaceutical preparations may be prepared followingconventional techniques of the pharmaceutical chemist involving stepssuch as mixing, granulating, and compressing when necessary for tabletforms, or mixing, filling, and dissolving the ingredients asappropriate, to give the desired products for oral, parenteral, topical,intravaginal, intranasal, intrabronchial, intraocular, intraaural,and/or rectal administration.

[0350] The compounds (active ingredients) may be formulated into solidoral dosage forms which may contain, but are not limited to, thefollowing inactive ingredients: diluents (i.e., lactose, corn starch,microcrystalline cellulose), binders (i.e., povidone, hydroxypropylmethylcellulose), disintegrants (i.e., crospovidone, croscarmellosesodium), lubricants (i.e., magnesium stearate, stearic acid), andcolorants (FD&C lakes or dyes). Alternatively, the compounds may beformulated into other oral dosage forms including liquids, suspensions,emulsions, or soft gelatin capsules, with each dosage form having aunique set of ingredients.

[0351] Solid or liquid pharmaceutically acceptable carriers, diluents,vehicles, or excipients may be employed in the pharmaceuticalcompositions. Illustrative solid carriers include starch, lactose,calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, pectin,acacia, magnesium stearate, and stearic acid. Illustrative liquidcarriers include syrup, peanut oil, olive oil, saline solution, andwater. The carrier or diluent may include a suitable prolonged-releasematerial, such as glyceryl monostearate or glyceryl distearate, alone orwith a wax. When a liquid carrier is used, the preparation may be in theform of a syrup, elixir, emulsion, soft gelatin capsule, sterileinjectable liquid (e.g., solution), or a nonaqueous or aqueous liquidsuspension. A dose of the pharmaceutical composition contains at least atherapeutically effective amount of the active compound (i.e., acompound of Formulas I to XII or a pharmaceutically acceptable salt,prodrug, active metabolite, or solvate thereof), and preferably is madeup of one or more pharmaceutical dosage units. The selected dose may beadministered to a mammal, for example, a human patient, in need oftreatment mediated by inhibition of picornaviral 3C protease activity,by any known or suitable method of administering the dose, including:topically, for example, as an ointment or cream; orally; rectally, forexample, as a suppository; parenterally by injection; or continuously byintravaginal, intranasal, intrabronchial, intraaural, or intraocularinfusion. A “therapeutically effective amount” is intended to mean theamount of an inventive agent that, when administered to a mammal in needthereof, is sufficient to effect treatment for disease conditionsalleviated by the inhibition of the activity of one or more picornaviral3C proteases, such as human rhinoviruses, human poliovirus, humancoxsackieviruses, encephalomyocarditis viruses, menigovirus, andhepatitis A virus. The amount of a given compound of the invention thatwill be therapeutically effective will vary depending upon factors suchas the particular compound, the disease condition and the severitythereof, the identity of the mammal in need thereof, which amount may beroutinely determined by artisans.

GENERAL SYNTHETIC METHODS

[0352] Preferably, compounds of the general formulas are prepared by themethods of the present invention, including the General Methods below,where the R¹, R⁴, R⁵, R⁶, Z and Z¹ substituents present in the compoundsillustrated in the General and Specific Methods are as defined above.Abbreviations used herein include: DCC (1,3-dicyclohexylcarbodiimide),HOBT (1-hydroxybenzotriazole hydrate), HATU(O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate), IBX (2-iodoxybenzoic acid), FMOC(9-fluorenylmethoxycarbonyl), Boc (t-butoxycarbonyl), DIEA(diisopropylethylamine), DMSO (dimethylsulfoxide), TMSOTf(trimethylsilyl trifluoromethanesulfonate), TFA (trifluoroacetic acid),LiHMDS (lithium bis(trimethylsilyl)amide).

[0353] In General Method 1, a sidechain protected (P) compound 1(Dragovich, et al., J. Med. Chem. 1998, 41, 2819), is coupled usingstandard peptide coupling methods, to another amino acid with adifferent protecting group (P′) on the alpha-nitrogen, to givedi-peptide compound 2. The P′ protecting group is then selectivelyremoved, and the resulting amine is coupled to a substitutedpyrrole-2-carboxylic acid (prepared as described in General Methods 4,5, and 6), or a suitably activated analog of this acid, such as an acidchloride, ester or amide (X¹=OH, halo, etc.), to give 3. Thesidechain-protecting group P is then removed to give 4. These compoundsmay also be made using solid phase synthetic techniques (Dragovich, etal., Bioorg. Med. Chem., 1999 7, 589), where protecting group Pconstitutes a linker (such as the Rink linker) attached to solid phaseresin.

[0354] In General Method 2, compound 5 (prepared by a method analogousto that described in Tian, et al., U.S. Provisional Patent ApplicationNo. 60/150,358, filed Aug. 24, 1999 (now U.S. patent application Ser.No. 09/643,864) and also Baldwin et al., J. Org. Chem., 1971, 36, 1441)is coupled to another amino acid with sidechain protecting group P togive 6. The protecting group of 6 is removed, and the liberated amine iscoupled to a 5-substituted pyrrole-2-carboxylic acid (prepared asdescribed in General Methods 4, 5, and 6) via a suitably activatedanalog of this acid, such as an acid chloride, ester or amide (X¹=OH,halo, etc.), to give compound 7.

[0355] In General Method 3, compound 5 is coupled to carboxylic acids ofthe type 8 (prepared as described in General Methods 7 and 8), where W═Nor CH, to give compound 9.

[0356] In General Method 4, 2,5-disubstituted pyrroles are prepared bybromination of pyrrole-2-carboxylic acid ester 10, where R is an alkylor aryl group, which is unsubstituted or substituted with one or moresuitable substituents, to give 11, followed by a transition-metalmediated carbon-carbon bond forming reaction (for example, using Pd⁰with an appropriate ligand such as triphenylphosine or triphenylarsine)with an organometallic species, R¹M (for example, an organoboronic acidor an organotin compound) to give 12.

[0357] General Method 5 depicts another method used to make2,5-disubstituted pyrroles, analogous to the method described by Kruse,et al., Heterocycles, 1987, 26, 3141. A carboxylic acid 13 is convertedto a suitably activated species 14 (X²=a Weinreb amide (—N(OCH₃)CH₃),halo, etc.) then reacted with a nucleophilic organometallic compoundcontaining a protected aldehyde to provide 15. The aldehyde isdeprotected to give 16, then is condensed with an ammonia equivalentsuch as ammonium chloride, to provide pyrrole 17. This pyrrole is thenreacted with a phosgene-type equivalent such as trichloroacetyl chloride(analogous to the method described by Bailey, et al., Org. Synth., 1971,51, 100), to provide the 2,5-disubstituted pyrrole 18. (X¹=OH, halo,etc.).

[0358] General Method 6 shows an alternate method to make2,5-disubstituted pyrroles. Aldehyde 19 is reacted with a nucleophilicorganometallic compound containing a protected aldehyde to providealcohol 20. The alcohol is then oxidized to ketone 15 using standardmethodology such as a Swern oxidation. Ketone 15 is carried on topyrrole 18 using the same method as shown in General Method 5.

[0359] General Method 7 depicts the preparation of a pyrrole containingthe keto-methylene moiety, 27, analogous to the method described byGonzalez-Muniz et. al. (Gonzalez-Muniz, et al., Tetrahedron, 1992, 48,5191; Garcia-Lopez, et al., Tetrahedron Lett., 1988, 29, 1577;Garcia-Lopez, et al., Tetrahedron, 1988, 44, 5138). Carboxylic acid 21is converted to a suitably reactive intermediate 22 such as a Weinrebamide, acid chloride or ester (X²=N(OCH₃)CH₃, halo, etc.), then reactedwith an organometallic reagent (R⁴M, such as methyllithium) to givepyrrole-acetone compound 23. This compound is then halogenated to give24 (where X³=halo), then reacted with a malonate salt (R′=alkyl) to give25. This compound is deprotonated by treatment with a strong base, thenreacted with an electrophile (R⁵-X³) to give 26. Decarboxylation ofcompound 26 gives product 27.

[0360] General Method 8 shows the preparation of an optically activepyrrole containing the keto-methylene moiety, compound 33. Carboxylicacid 28 is converted to chiral amide 29, by coupling to a chiral amineor oxazolidinone, N_(c), that is known to control enolate alkylationdiastereoselectivity. Compound 29 is deprotonated, then reacted with anelectrophile such as t-butyl bromoacetate, analogous to the methoddescribed by Charlton, et al., Can. J. Chem. 1997, 75, 1076, to give 30.The chiral auxiliary is removed, and the resulting acid is esterified togive 31. The R′ ester of 31 is selectively removed, and the resultingacid is converted to the disubstituted amide 32, by coupling to asecondary amine. Compound 32 is reacted with pyrrole 17, under typicalVilsmeier reaction conditions (Silverstein, et al., Org. Synth., 1963,Coll. Vol. IV, 831) to give pyrrole 33. As used herein, R′, R″ and R′″are each independently lower alkyl, which is unsubstituted orsubstituted with one or more suitable substituents,

[0361] In General Method 9, a pyrrole-carboxylic acid 34 (commerciallyavailable or prepared by methods described in the chemical literature oras prepared as described in General Methods 4, 5 and 6), where R¹ is asdefined above, is transformed into ketoester 35. Compound 35 issubsequently deprotonated and coupled with triflate 37 (whichincorporates R⁵ and which can be prepared from hydroxy-ester 36, whereR″″ is alkyl or cycloalkyl, e.g., lower alkyl, allyl, benzyl, or C₃-C₆cycloalkyl, which are unsubstituted or substituted with one or moresuitable substituents) to afford intermediate 38 after acid-effecteddecarboxylation. Intermediate 38 is related to compound 32 (GeneralMethod 8) and may be utilized in any of the previously described generalsyntheses where appropriate. Note that the NH present inpyrrole-carboxylic acid 34 may also be protected with a suitableprotecting group which may be removed at any time during the synthesisof 38. The methodology for converting pyrrole-carboxylic acid 34 tointermediate 38 is generally described in: Hoffman, R. V.; Tao, J.Tetrahedron 1997, 53, 7119-7126.

[0362] In General Method 10, an amino acid 39 (or salt thereof) whichincorporates R⁵ is transformed into hydroxy acid 40. This intermediateis subsequently converted to hydroxy ester 41 which may be utilized inGeneral Method 9 above for the preparation of the compounds described inthis invention.

SPECIFIC METHODS

[0363]

[0364] Specific Method 1 describes the preparation of compoundscontaining a glutamine residue in the P-1 position.FMOC-4-amino-hept-2(trans)-enedioic acid -1 ethyl ester 42 (Dragovich,et al., J. Med. Chem. 1998, 41, 2819) was coupled to Rink polystyreneutilizing HATU as a coupling reagent to get 43. The FMOC protectinggroup was removed with piperidine, and the liberated amine was thencoupled to an FMOC-protected amino acid 44 to get compound 45. The FMOCof 45 was again removed with piperidine, and the free amine was acylatedwith a 5-substituted-2-pyrrole carboxylic acid chloride 46 (prepared asdescribed in Specific Methods 4, 5, and 6). The final compound, 37, wascleaved from the resin with trifluoroacetic acid, to give compound 48.

[0365] Specific Method 2 describes the synthesis of compounds containingthe oxo-pyrrolidine sidechain in the P-1 position. Boc-protected4S-amino-5-(2-oxo-pyrrolidin-3S-yl)-pent-2(trans)-enoic acid ethyl ester49 (prepared by a method analogous to that described in Tian, et al.,U.S. Provisional Patent Application No. 60/150,358, filed Aug. 24, 1999and also Baldwin et al., J. Org. Chem., 1971, 36, 1441) was deprotectedwith HCl, then coupled using HATU to a Boc-protected amino acid 50. TheBoc-protected product 51 was treated with HCl, then coupled to a5-substituted-pyrrole-2-carboxylic acid chloride 46 (prepared asdescribed in Specific Methods 4, 5, and 6), to produce product 52.

[0366] Specific Method 3 describes the preparation of compoundscontaining the pyrrole-ketomethylene moiety. Boc-protected4S-amino-5-(2-oxo-pyrrolidin-3S-yl)-pent-2(trans)-enoic acid ethyl ester49 was deprotected with HCl, then coupled to acid 53 (prepared asdescribed in Specific Method 7 and 8), using HATU, to provide compound54.

[0367] Specific Method 4 describes the synthesis of5-substituted-pyrrole-2-carboxylic acid chlorides. Pyrrole-2-carboxylicacid 55 was esterified with diazomethane, to give methyl ester 56, thenbrominated with N-bromosuccinimide to give 5-bromopyrrole 57. Thebromide was reacted with a boronic acid using standard Suzuki couplingconditions to give 58. The methyl ester was cleaved with lithiumhydroxide, and the resulting acid was converted to the acid chloride 46using oxalyl chloride.

[0368] Specific Method 5 describes an alternate method of pyrrolesynthesis. Carboxylic acid 59 was converted to an acid chloride usingoxalyl chloride, then converted to the N-methoxy-N-methyl amide withO,N-dimethyl hydroxylamine. This amide 60 was reacted with Grignardreagent 61 to give ketone 62. The dioxolane-protecting group wasconverted to the corresponding aldehyde with aqueous HCl, then condensedwith ammonium chloride to give pyrrole 63. This pyrrole was reacted withtrichloroacetyl chloride to give the disubstituted pyrrole 64, which wasthen hydrodrolyzed to the corresponding carboxylic acid with lithiumhydroxide, then converted to the acid chloride 46 using oxalyl chloride.

[0369] Specific Method 6 describes an alternate method of pyrrolesynthesis. Aldehyde 65 was reacted with Grignard reagent 61 to givealcohol 66. This alcohol was subjected to Swern oxidation conditions toprovide ketone 62, which was converted to the acid chloride 46 accordingto Specific Method 5.

[0370] Specific Method 7 describes the synthesis of a racemicpyrrole-ketomethylene compound. 5-Substituted-pyrrole-2-carboxylic acid67 (prepared as described in Specific Methods 4, 5 and 6) was convertedto the Weinreb amide 68 using standard conditions, then treated withmethyllithium to give pyrrole-acetone 69. This ketone was converted toits silyl-enol ether with trimethylsilyl triflate, then brominated withN-bromosuccinimide to give bromide 70. The bromide was displaced withsodium diethylmalonate to give malonate 71. The sodium enolate of thiscompound was alkylated to give 72, which was then de-esterified andde-carboxylated to give carboxylic acid 53.

[0371] Specific Method 8 describes the enantioselective preparation of apyrrole-ketomethylene compound. Carboxylic acid 73 was converted to thechiral amide 74 using standard conditions, then converted to its lithiumenolate and alkylated with t-butylbromoacetate to give 75. The chiralauxiliary was removed with lithium hydroperoxide, and the resulting acidwas esterified with diazomethane to give ester 76. The t-butylester wasselectively removed with trifluoroacetic acid, and the resulting acidwas converted to dimethyl amide 77 by treatment of the acid chloride(formed using oxalyl chloride) with dimethylamine hydrochloride. Amide77 was reacted with pyrrole 63 (prepared as described in SpecificMethods 4, 5 and 6) using standard Vilsmeier conditions to givepyrrole-ketomethylene 78. The methyl ester was cleaved with lithiumhydroxide to give carboxylic acid 79.

[0372] In Specific Method 9, H-D-propargyl glycine (80) (or a suitablesalt thereof) is treated with sodium nitrite under mildly acidic aqueousconditions to provide hydroxy acid 81 in good yield. This material isesterified by exposure to acidic methanol to give hydroxy ester 82.

[0373] In Specific Method 10, Boc-D-3,4-difluorophenylalanine 83 isdeprotected by treatment with trifluoroacetic acid in CH₂Cl₂ to affordamino acid TFA salt 84. This intermediate is treated with sodium nitriteunder mildly acidic aqueous conditions to provide hydroxy acid 85 ingood yield. Compound 85 is esterified by exposure to either methanol orbenzyl alcohol under acidic conditions to give hydroxy esters 86 and 87,respectively.

[0374] In Specific Method 11, 2-ketobutyric acid (88) is subjected to anenzyme-mediated reduction process to afford hydroxy acid 89 in goodyield.

EXAMPLES

[0375] Examples of the processes used to make several of the compoundsof Formulas I and II are set forth below. The structures of thecompounds of the following examples were confirmed by one or more of thefollowing: proton magnetic resonance spectroscopy, infraredspectroscopy, elemental microanalysis and melting point. Proton magneticresonance (¹H NMR) spectra were determined using either a VarianUNITYplus 300 or a General Electric QE-300 spectrometer operating at afield strength of 300 megahertz (MHz). Chemical shifts are reported inparts per million (ppm, δ) downfield from an internal tetramethylsilanestandard. Alternatively, ¹H NMR spectra were referenced to residualprotic solvent signals as follows: CHCl₃=7.26 ppm; DMSO=2.49 ppm,C₆HD₅=7.15 ppm. Peak multiplicities are designated as follows: s,singlet; d, doublet; dd, doublet of doublets; t, triplet; q, quartet;br, broad resonance; m, multiplet. Coupling constants are given inHertz. Infrared absorption (IR) spectra were obtained using aPerkin-Elmer 1600 series FTIR spectrometer. Elemental microanalyses wereperformed by Atlantic Microlab Inc., Norcross, Ga. and gave results forthe elements stated within ±0.4% of the theoretical values. Flash columnchromatography was conducted using Silica gel 60 (Merck Art 9385).Analytical thin layer chromatography (TLC) was conducted using precoatedsheets of Silica 60 F₂₅₄ (Merck Art 5719). Melting points weredetermined on a Mel-Temp apparatus and are uncorrected. All reactionswere conducted in septum-sealed flasks under a slight positive pressureof argon unless otherwise noted. All commercial reagents were used asreceived from their respective suppliers with the following exceptions.Tetrahydrofuran (THF) was distilled from sodium-benzophenone ketyl priorto use. Dichloromethane (CH₂Cl₂) was distilled from calcium hydrideprior to use. The abbreviations used herein include: Et₂O (diethylether), DMF (N,N-dimethylformamide), DMSO (dimethylsulfoxide), MTBE(tert-butyl methyl ether), CH₃OH (methanol), EtOH (ethanol), EtOAc(ethyl acetate), DME (ethylene glycol dimethyl ether) Ac (acetyl), Me(methyl), Ph (phenyl), Tr (triphenylmethyl), Cbz (benzyloxycarbonyl),Boc (tert-butoxycarbonyl), TFA (trifluoroacetic acid), DIEA(N,N-diisopropylethylamine), TMEDA(N,N,N′,N′-tetramethylethylenediamine), AcOH (acetic acid), Ac₂O (aceticanhydride), NMM (4-methylmorpholine), HOBt (1-hydroxybenzotriazolehydrate), HATU (O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate), EDC(1-(3-dimethylaminopropyl)-3-ethylcarbarbodiimide hydrochloride), DCC(dicyclohexyl-carbodiimide), DDQ(2,3-dichloro-5,6-dicyano-1,4-benzoquinone), DMAP(4-dimethylaminopyridine), Gln (glutamine), Leu (leucine), Phe(phenylalanine), Phe(4-F) (4-fluorophenylalanine), Val (valine),amino-Ala (2,3-diaminopropionic acid), and(S)-Pyrrol-Ala((2S,3′S)-2-amino-3-(2′-oxopyrrolidin-3′-yl)-propionicacid). Additionally, “L” represents the configuration of naturallyoccurring amino acids.

Example 1 Preparation of Gln-resin and Phe-Gln Resin

[0376] Fmoc-Rink polystyrene resin (1.58 mmol, 2.40 g) was treated witha 1:1 solution of DMF-piperidine (25 ml) in a shaker vessel, to removethe Fmoc. The resulting slurry was agitated for 15 min, then washed withDMF (3×10 ml). The resin was then treated with a solution ofFmoc-4-amino-hept-2(trans)-enedioic acid-1-ethyl ester^(1a,b) (2.37mmol, 1.00 g), DIEA (4.74 mmol, 0.82 ml), and HATU (2.37 mmol, 0.90 g)in DMF (25 ml). The resulting mixture was agitated for 1 h, then washedwith DMF (3×10 ml). The Fmoc was then removed by treatment with asolution of 20% piperidine-DMF (25 ml), and agitation for 10 min. Theresulting resin was washed with DMF (3×10 ml), MeOH (3×10 ml), andCH₂Cl₂ (3×10 ml). (The resin at this stage will be hereafter referred toas Gin-resin) The Gln-resin was then treated with a solution ofFmoc-phenylalanine (4.74 mmol, 1.84 g), DIEA (9.48 mmol, 1.65 ml), andHATU (4.74 mmol, 1.80 g) in DMF (25 ml). The resulting mixture wasagitated for 1 h, then washed with DMF (3×25 ml). The Fmoc was removedby treatment with a solution of 20% piperidine-DMF (25 ml), thenagitation for 10 min. The resin was washed with DMF (3×10 ml), MeOH(3×10 ml), and CH₂Cl₂ (3×10 ml). The resin was then dried in a vacuumdesiccator. (The resin at this stage will be hereafter referred to asPhe-Gln-resin).

Example 26-Carbamoyl-4S-{2S-[(5-naphthalen-1-yl-1H-pyrrole-2-carbonyl)-amino-3-phenyl-propionylamino}-hex-2(trans)-enoicAcid Ethyl Ester. (Compound 3)

[0377]

[0378] 5-Naphthalen-1-yl-1H-pyrrole-2-carboxylic Acid Chloride

[0379] Method 4 General Experimental: Pyrrole-2-carboxylic acid (90.0mmol, 10.0 g) in diethyl ether (200 ml) was treated with diazomethane(270 mmol, generated from N-nitroso-N-methyl urea), then back titratedwith acetic acid until the yellow color dissipated. The solution waswashed with saturated aqueous sodium bicarbonate (3×20 ml) and brine(3×20 ml), then concentrated under reduced pressure to provide 10 g(88%) of pyrrole-2-carboxylic acid methyl ester. ¹H NMR (CDCl₃) δ 9.14(1H, s), 6.98-6.65 (1H, m), 6.94-6.91 (1H, m), 6.29-6.26 (1H, m), 3.86(3H, s).

[0380] A solution of pyrrole-2-carboxylic acid methyl ester (79.9 mmol,10.0 g) in carbon tetrachloride (300 ml) was heated to 70° C., thentreated dropwise with a solution of bromine (99.9 mmol, 126.0 ml) incarbon tetrachloride (200 ml). The reaction was initiated by theaddition of iodine (40 mg). After the addition was complete, thereaction was held at 70° C. for 10 min, then cooled to room temperatureusing an ice bath. The mixture was washed with 10% aqueous sodiumcarbonate (100 ml), followed by water (100 ml). The organics wereconcentrated under reduced pressure and the residue was purified bysilica gel chromatography to provide 4.5 g (27%) of5-bromo-1H-pyrrole-2-carboxylic acid methyl ester. ¹H NMR (CDCl₃) δ 9.29(1H, s), 6.80 (1H, dd, J=3.9, 2.7), 6.23 (1H, dd, J=3.8, 2.6), 3.88 (3H,s).

[0381] Argon gas was bubbled 15 min through a solution of5-bromo-1H-pyrrole-2-carboxylic acid methyl ester (10.0 mmol, 2.04 g),1-naphthylboronic acid (30.0 mmol, 5.16 g), 2M aqueous sodium carbonate(20 ml), and DMF (150 ml). The mixture was then treated withtris(dibenzylidienacetone)dipalladium (0) (0.50 mmol, 0.46 g), andtriphenylarsine (2.0 mmol, 0.61 g), then heated to reflux under argonfor 12 h. The mixture was partitioned between ethyl acetate (500 ml) andwater (150 ml). The organics were filtered through celite, washed withbrine (3×50 ml), then concentrated under reduced pressure and theresidue was purified by silica gel chromatography to provide 2.05 g(81%) of 5-naphthalen-1-yl-1H-pyrrole-2-carboxylic acid methyl ester. ¹HNMR (CDCl₃) δ 9.37 (1H, s), 8.22-8.17 (1H, m), 8.16-7.89 (2H, m),7.59-7.50 (4H, m), 7.88 (1H, dd, J=3.9, 2.7), 6.22 (1H, dd, J=3.8. 2.6),3.88 (3H, s).

[0382] 5-Naphthalen-1-yl-1H-pyrrole-2-carboxylic acid methyl ester wasdiluted with 1:1 dioxane-water (30 ml), and treated with lithiumhydroxide hydrate (24.4 mmol, 1.02 g), then heated to reflux for 15 min.The solution was acidified with 20% aqueous citric acid (30 ml), thenextracted with ethyl acetate (75 ml). The organics were washed withbrine (2×20 ml), then concentrated under reduced pressure. The residuewas diluted with CH₂Cl₂, (30 ml), and treated with oxalyl chloride (24.0mmol, 2.10 ml), and DMF (one drop), then heated to reflux for 30 min.The solution was concentrated under reduced pressure to provide 1.95 gof 5-naphthalen-1-yl-1H-pyrrole-2-carboxylic acid chloride.

[0383] Method 1 General Experimental:5-Naphthalen-1-yl-1H-pyrrole-2-carboxylic acid chloride (0.75 mmol, 0.19g, prepared as described above) in CH₂Cl₂ (10 ml) and collidine (3.75mmol, 0.50 ml) was added to Phe-Gln-resin, prepared as described inExample 1, (0.38 mmol, 0.51 g), and agitated for 1 h. The resin was thenwashed with CH₂Cl₂ (3×10 ml), then suspended in a solution of 95:5TFA—CH₂Cl₂ (10 ml) and stirred vigorously. The resin was separated byfiltration, and the filtrate was concentrated under reduced pressure.The resulting oil was purified by preparative reverse phasechromatography (H₂O—CH₃CN gradient) to provide 21 mg (10%) of the titleproduct. ¹H NMR (CDCl₃) δ 10.55 (1H, br s), 8.16-8.08 (1H, m), 7.83-7.73(2H, m), 7.48-7.36 (4H, m), 7.27-7.11 (5H, m), 6.88 (1H, dd, J=3.7,2.5), 6.54 (1H, dd, J=15.7, 5.4), 6.41 (1H, dd, J=3.7, 2.5), 5.46 (1H,dd, J=15.7, 1.6), 4.62 (1H, t, J=7.2), 4.45-4.35 (1H, m), 4.09 (2H, q,J=7.2), 3.05-2.99 (2H, m), 2.19-2.11 (2H, m), 1.92-1.80 (1H, m),1.68-1.54 (1H, m), 1.21 (3H, t, J=7.2). HRMS (FAB) 589.2427 (MNa⁺,calcd. 589.2447).

Example 36-Carbamoyl-4S-(2S-{[5-(2,3-dichloro-phenyl)-1H-pyrrole-2-carbonyl]-amino}-3-phenyl-propionylamino-hex-2(trans)-enoicAcid Ethyl Ester. (Compound 1)

[0384]

[0385] 5-(2,3-Dichloro-phenyl)-1H-pyrrole-2-carboxylic acid chloride wasprepared according to the procedure described in Method 4 of Example 2,starting with 2,3-dichlorophenyl boronic acid. This material was coupledto Phe-Gln resin and converted to the title compound according to theprocedure described in Method 1 of Example 2. ¹H NMR (CD₃OD) δ 7.52-7.44(2H, m), 7.36-7.16 (6H, m), 6.83 (1H, d, J=3.9), 6.64 (1H, dd, J=15.8,5.7), 6.54 (1H, d, J=3.9), 5.57 (1H, d, J=6.0), 4.68 (1H, t, J=7.7),4.53-4.42 (1H, m), 4.17 (2H, q, J=7.1), 3.19-3.03 (2H, m), 2.28 (2H, t,J=7.9), 1.99-1.85 (1H, m), 1.78-1.65 (1H, m), 1.28 (3H, t, J=7.1). HRMS(MALDI) 607.1501 (MNa⁺, calcd. 607.1491).

Example 46-Carbamoyl-4S-{3-phenyl-2S-[(5-(2-trifluoromethyl-phenyl)-1H-pyrrole-2-carbonyl)-amino]-propionylamino}-hex-2(trans)-enoicAcid Ethyl Ester. (Compound 2)

[0386]

[0387] 5-(2-Trifluoromethyl-phenyl)-1H-pyrrole-2-carboxylic AcidChloride.

[0388] Method 6 General Experimental: Magnesium (230.0 mmol, 5.6 g) inTHF (200 ml), under an argon atmosphere, was treated with2-(2-bromoethyl)-1,3-dioxolane (200.0 mmol, 23.5 ml), slowly, keepingthe internal temperature below 35° C. with the aid of an ice bath. Aftercompletion of the addition, the mixture was held at room temperature foran additional 1 h. 2-Trifluoromethyl benzaldehyde (100 mmol, 13.2 ml) inTHF (100 ml) was cooled to −78° C. under an argon atmosphere, thentreated with the freshly formed Grignard reagent prepared above. Aftercompletion of the addition, the solution was allowed to warm to roomtemperature, then held at room temperature overnight. The reactionmixture was then poured into saturated aqueous NH₄Cl (200 ml), andextracted with ethyl acetate (2×150 ml). The combined organics werewashed with brine (2×75 ml), then concentrated under reduced pressure togive 32.8 g of3-[1,3]dioxolan-2-yl-1-(2-trifluoromethyl-phenyl)-propan-1-ol, which maybe used without further purification. ¹H NMR (CDCl₃) δ 7.78 (1H, d,J=7.7), 7.62-7.52 (2H, m), 7.34 (1H, t, J=7.6), 4.92 (1H, t, J=4.0),4.00-3.81 (5H, m), 1.90-1.80 (4H, m).

[0389] Oxalyl chloride (115.0 mmol, 10.0 ml) in CH₂Cl₂ (200 ml) wascooled to −78° C. under an argon atmosphere. DMSO (240.0 mmol, 17.0 ml)was then added slowly, keeping the internal temperature below −50° C.After completing the addition, the solution was held 20 minutes at −78°C. 3-[1,3]Dioxolan-2-yl-1-(2-trifluoromethyl-phenyl)-propan-1-ol (32.8 gof crude material prepared above) in CH₂Cl₂ (30 ml) was added slowly,keeping the internal temperature below −50° C. The mixture was held at−78° C. for 30 minutes, then treated with Et₃N (480 mmol, 70.0 ml). Themixture was allowed to warm to room temperature, then washed with water(2×75 ml), then concentrated under reduced pressure to give crude3-[1,3]dioxolan-2-yl-1-(2-trifluoromethyl-phenyl)-propan-1-one, whichmay be used without further purification. ¹H NMR (CDCl₃) δ 7.00 (1H, d,J=7.7), 7.63-7.50 (2H, m), 7.44 (1H, d, J=7.4), 4.99 (1H, t, J=4.3),3.97-3.82 (4H, m), 2.98 (2H, t, J=7.3) 2.12 (2H, dt, J=7.4, 4.3).

[0390] The crude product3-[1,3]dioxolan-2-yl-1-(2-trifluoromethyl-phenyl)-propan-1-one, in itsentirety, was treated with 1:1 2N HCl:dioxane (150 ml), then heated toreflux for 20 minutes. The resulting mixture was extracted with ethylacetate (2×150 ml). The combined organics were washed with brine (2×75ml), then concentrated under reduced pressure to give crude4-oxo-4-(2-trifluoromethyl-phenyl)-butyrylaldehyde, which may be usedwithout further purification. 1H NMR (CDCl₃) δ 9.89 (1H, s), 7.71 (1H,d, J=7.5), 7.66-7.52 (3H, m), 3.15 (2H, t, J=6.1), 3.01-2.92 (2H, m).

[0391] The above prepared4-oxo-4-(2-trifluoromethyl-phenyl)-butyrylaldehyde was diluted withethanol (300 ml), and treated with ammonium acetate (1.00 mol, 53.5 g),then heated to reflux for 1 h. This mixture was diluted with ethylacetate (500 ml) and washed with brine (2×75 ml). The organics wereconcentrated under reduced pressure and the residue was purified bysilica gel chromatography to provide 7.8 g (37% from 2-trifluoromethylbenzaldehyde) of 2-(2-trifluoromethyl-phenyl)-1H-pyrrole. ¹H NMR (CDCl₃)δ 8.51 (1H, br s), 7.74 (1H, d, J=7.9), 7.60-7.54 (2H, m), 7.44-7.36(1H, m), 6.95-6.91 (1H, m), 6.44-6.41 (1H, m), 6.33 (1H, dd, J=6.0,2.6).

[0392] This material was treated with trichloroacetyl chloride,hydrolyzed with lithium hydroxide, and converted to the correspondingacid chloride using oxalyl chloride, as described in Method 5 of Example12, to give 5-(2-trifluoromethyl-phenyl)-1H-pyrrole-2-carboxylic acidchloride. ¹H NMR (CDCl₃) δ 9.35 (1H, s), 7.80 (1H, d, J=7.4), 7.68-7.52(3H, m), 7.26-7.23 (1H, m), 7.53-7.49 (1H, m).

[0393] 5-(2-Trifluoromethyl-phenyl)-1H-pyrrole-2-carboxylic acidchloride was coupled to Phe-Gln-resin, and converted to the titlecompound according to the procedure described in Method 1 of Example 2.¹H NMR (CDCl₃) δ 10.10 (1H, br s), 7.21 (1H, d, J=7.8), 7.59-7.40 (3H,m), 7.32-7.16 (5H, m), 6.82-6.76 (1H, m), 6.61 (1H, dd, J=15.8, 5.2),6.39-6.33 (1H, m), 5.55 (1H, d, J=15.7), 4.69 (1H, t, J=7.2), 4.54-4.43(1H, m), 4.16 (2H, q, J=7.1), 3.09 (2H, d, J=7.0), 2.25-2.15 (2H, m),2.20-1.85 (1H, m), 1.78-1.52 (1H, m), 1.27 (3H, t, J=7.1). HRMS (FAB)607.2128 (MNa⁺, calcd. 607.2144).

Example 56-Carbamoyl-4S-(2S-{[5-(5-chloro-2-methoxy-phenyl)-1H-pyrrole-2-carbonyl]amino}-3-phenyl-propionylamino)-hex-2(trans)-enoicAcid Ethyl Ester (Compound 4)

[0394]

[0395] 5-(5-Chloro-2-methoxy-phenyl)-1H-pyrrole-2-carboxylic acidchloride was prepared according to the procedure described in Method 4of Example 2, starting with 5-chloro-2-methoxyphenyl boronic acid. Thismaterial was coupled to Phe-Gln resin, and converted to the titlecompound according to the procedure described in Method 1 of Example 2.¹H NMR (CDCl₃) δ 10.50 (1H, br s), 7.56 (1H, d, J=2.6), 7.30-7.12 (6H,m), 6.88 (1H, d, J=8.9), 6.79-6.75 (1H, m), 6.60 (1H, dd, J=15.7, 5.3),6.58-6.55 (1H, m), 5.54 (1H, dd, J=15.7, 1.5), 4.73-4.65 (1H, m),4.53-4.43 (1H, m), 4.16 (2H, q, J=7.1), 3.93 (3H, s,), 3.14-3.04 (2H,m), 2.23-2.15 (2H, m), 1.99-1.84 (1H, m), 1.78-1.62 (1H, m), 1.27 (3H,t, J=7.1). HRMS (FAB) 603.1963 (MNa⁺, calc. 603.1986).

Example 66-Carbamoyl-4S-{2S-[(5-isoquinolin-4-yl-1H-pyrrole-2-carbonyl)-amino]-3-phenyl-propionylamino}-hex-2(trans)-enoicAcid Ethyl Ester. (Compound 5)

[0396]

[0397] 4-Bromoisoquinoline (4.10 mmol, 0.85 g) in toluene (15 ml) wastreated with hexamethylditin (5.6 mmol, 2.00 g), andtetrakis(triphenylphosphine)-palladium(0) (0.20 mmol, 0.24 g), thenheated to reflux overnight under an argon atmosphere. The resultingmixture was concentrated under reduced pressure, then purified by silicagel chromatography to provide 1.03 g (87%) of4-(trimethylstannyl)-isoquinoline. ¹H NMR (CDCl₃) δ 9.23 (1H, s), 8.52(1H, s), 8.00 (1H, d, J=8.1), 7.78-7.62 (3H, m), 0.5 (9H, s).

[0398] 5-Bromo-1H-pyrrole-2-carboxylic acid methyl ester (1.49 mmol,0.30 g, prepared according to the procedure described in Method 4 ofExample 2) in NMP (10 ml) was treated with triphenylarsine (0.30 mmol,91 mg), tris(dibenzylideneacetone) dipalladium(0) (0.07 mmol, 68 mg),and 4-(trimethylstannyl)-isoquinoline (2.22 mmol, 0.65 g), then heatedto reflux under an argon atmosphere overnight. The resulting mixture wasconcentrated under reduced pressure, then purified by silica gelchromatography to provide 0.21 g (55%) of5-isoquinolin-4-yl-1H-pyrrole-2-carboxylic acid methyl ester. ¹H NMR(CDCl₃) δ 9.81 (1H, br s), 9.35 (1H, s), 8.66 (1H, s), 8.31 (1H, d,J=8.5), 8.10 (1H, d, J=8.1), 7.91 (1H, t, J=15.2), 7.79 (1H, t, J=15.2),7.11 (1H, dd, J=3.8, 2.5), 6.64 (1H, dd, J=3.7, 2.7), 3.90 (3H, s).

[0399] This material was converted to5-isoquinolin-4-yl-1H-pyrrole-2-carboxylic acid chloride according tothe procedures described in Method 4 of Example 2. This material wasthen coupled to Phe-Gln resin, and converted to the title compoundaccording to the procedure of Method 1 of Example 2. ¹H NMR (CD₃OD) δ9.20 (1H, br s), 8.51 (1H, s), 8.27 (1H, d, J=8.6), 8.17 (1H, d, J=8.1),7.85 (1H, t, J=8.4), 7.74 (1H, t, J=8.2), 7.30-7.17 (9H, m), 7.07 (1H,d, J=3.8), 6.65 (1H, dd, J=15.8, 5.6), 6.56 (1H, d, J=3.8), 5.58 (1H, d,J=15.8), 4.55-4.46 (1H, m), 4.18 (2H, q, J=7.1), 3.17 (2H, t, J=7.8),2.29 (2H, q, J=7.9), 2.24-1.68 (4H, m), 1.31 (3H, t, J=7.1). HRMS (FAB)590.2363 (MNa⁺, calcd. 590.2379).

Example 76-Carbamoyl-4S-(2S-{[5-(3-isopropyl-phenyl)-1H-pyrrole-2-carbonyl]-amino}-3-phenyl-propionylamino)-hex-2(trans)-enoicAcid Ethyl Ester. (Compound 6)

[0400]

[0401] 5-(3-iso-Propyl-phenyl)-1H-pyrrole-2-carboxylic acid chloride wasprepared according to the procedure described in Method 4 of Example 2,starting with 3-isopropylphenyl boronic acid. This product was coupledto Phe-Gln resin, according to the procedure described in Method 1 ofExample 2. 1H NMR (CD₃OD) δ 11.13 (1H, br s), 7.53 (1H, s), 7.47 (1H, d,J=7.9), 7.32-7.26 (5H, m), 7.25-7.18 (1H, m), 7.14 (1H, d, J=7.8), 6.93(1H, dd, J=3.7, 2.3), 6.65 (1H, dd, J=15.7, 5.6), 6.53 (1H, dd, J=3.8,2.4), 5.58 (1H, dd, J=15.7, 1.5), 4.71 (1H, t, J=7.7), 4.53-4.44 (1H,m), 4.18 (2H, q, J=7.1), 3.20-3.06 (2H, m), 2.94 (1H, d, J=6.9), 2.30(2H, t, J=7.2), 2.00-1.87 (1H, m), 1.80-1.66 (1H, m), 1.29 (3H, t,J=7.0), 1.28 (6H, d, J=7.0). HRMS (FAB) 581.2761 (MNa⁺, calcd.581.2740). Anal. (C₃₂H₃₈N₄O₅.0.7 H₂O) C, H, N.

Example 86-Carbamoyl-4S-(2S-{[5-(2,5-dimethoxy-phenyl)-1H-pyrrole-2-carbonyl]-amino}-3-phenyl-propionylamino)-hex-2-enoicAcid Ethyl Ester. (Compound 7)

[0402]

[0403] 5-(2,5-Dimethoxy-phenyl)-1H-pyrrole-2-carboxylic acid chloridewas prepared according to the procedure described in Method 4 of Example2, starting with 2,5-dimethoxyphenyl boronic acid. This material wascoupled to Phe-Gln resin, and converted to the title compound accordingto the procedure described in Method 1 of Example 2. ¹H NMR (CDCl₃) δ10.55 (1H, br s), 7.37-7.20 (7H, m), 6.90 (1H, d, J=9.0), 6.81 (1H, d,J=3.0), 6.65 (1H, dd, J=15.7, 5.3), 6.63-6.57 (1H, m), 5.61 (1H, dd,J=15.7, 1.5), 4.73-4.65 (1H, m), 4.53-4.43 (1H, m), 4.16 (2H, q, J=7.1),3.89 (3H, s), 3.80 (3H, s), 3.14-3.04 (2H, m), 2.35-2.20 (2H, m),2.10-1.85 (1H, m), 1.80-1.70 (1H, m), 1.27 (3H, t, J=7.1). HRMS (FAB)599.2499 (MNa⁺, calcd. 599.2482).

Example 96-Carbamoyl-4S-{3-phenyl-2S-[(5-o-tolyl-1H-pyrrole-2-carbonyl)-amino]-propionylamino}-hex-2(trans)-enoicAcid Ethyl Ester. (Compound 9)

[0404]

[0405] 5-(o-Tolyl)-1H-pyrrole-2-carboxylic acid chloride was preparedaccording to the procedure described in Method 4 of Example 2, startingwith o-tolyl boronic acid. This material was coupled to Phe-Gln resin,and converted to the title compound according to the procedure describedin Method 1 of Example 2. ¹H NMR (CDCl₃) δ 10.10 (1H, br s), 7.38-7.15(7H, m), 6.81 (1H, d, J=7.2), 6.77-6.70 (1H, m), 6.65-6.55 (2H, m), 6.29(1H, s), 5.58 (1H, d, J=15.5), 4.76-4.65 (1H, m), 4.58-4.45 (1H, m),4.18 (2H, q, J=7.1), 3.20-3.03 (2H, m), 2.20-2.00 (5H, m), 1.93-1.77(1H, m), 1.72-1.57 (1H, m), 1.90 (3H, t, J=7.1). HRMS (FAB) 553.2438(MNa⁺, calcd. 553.2427). Anal. (C₃₀H₃₄N₄O₅.1.0 H₂O) C, H, N.

Example 106-Carbamoyl-4S-{3-phenyl-2S-[(5-phenyl-1H-pyrrole-2-carbonyl)-amino]-propionylamino}-hex-2(trans)-enoicAcid Ethyl Ester. (Compound 10)

[0406]

[0407] 5-Phenyl-1H-pyrrole-2-carboxylic acid chloride was preparedaccording to the procedure described in Method 4 of Example 2, startingwith phenyl boronic acid. This material was coupled to Phe-Gln resin,and converted to the title compound according to the procedure describedin Method 1 of Example 2. ¹H NMR (CDCl₃) δ 11.15 (1H, br s), 8.27 (I1H,d, J=4.8), 7.67 (2H, d, J=7.3), 7.39 (2H, t, J=7.8), 7.33-7.19 (5H, m),7.76-7.71 (1H, m), 6.66 (1H, dd, J=15.7, 5.7), 6.57-6.53 (1H, m), 5.59(1H, d, J=15.7), 4.71 (1H, t, J=7.6), 4.55-4.45 (1H, m), 4.19 (2H, q,J=7.2), 3.33 (2H, q, J=8.3), 2.30 (2H, t, J=7.3), 2.03-1.87 (1H, m),1.80-1.68 (1H, m), 1.21 (3H, t, J=7.1). HRMS (FAB) 539.2283 (MNa⁺,calcd. 539.2270). Anal. (C₂₉H₃₂N₄O₅.0.7 H₂O+0.1 TFA), C, H, N.

Example 116-Carbamoyl-4S-(2S-{[5-(2-methoxy-phenyl)-1H-pyrrole-2-carbonyl]-amino}-3-phenyl-propionylamino)-hex-2(trans)-enoicAcid Ethyl Ester. (Compound 11)

[0408]

[0409] 5-(2-Methoxy-phenyl)-1H-pyrrole-2-carboxylic acid chloride wasprepared according to the procedure described in Method 4 of Example 2,starting with 2-methoxyphenyl boronic acid. This material was coupled toPhe-Gln resin, and converted to the title compound according to theprocedure described in Method 1 of Example 2. ¹H NMR (CDCl₃) δ 10.73(1H, s), 8.27 (1H, d, J=8.3), 7.69 (1H, d, J=7.6), 7.33-7.19 (5H, m),7.10 (1H, d, J=8.3), 7.01 (1H, t, J=7.7), 6.95 (1H, br s), 6.72-6.62(2H, m), 5.61 (1H, d, J=15.8), 4.72 (1H, t, J=7.2), 4.57-4.46 (1H, m),4.20 (2H, q, J=7.1), 3.99 (3H, s), 3.22-3.06 (2H, m), 2.32 (2H, t,J=7.4), 2.03-1.88 (1H, m), 1.82-1.70 (1H, m), 1.32 (3H, t, J=7.1). HRMS(MALDI) 569.2398 (MNa⁺, calcd. 569.2376). Anal. (C₃₀H₃₄N₄O₆.0.9 H₂O.0.4TFA) C, H, N.

Example 126-Carbamoyl-4S-(3-phenyl-2S-{[5-(3,3,3-trifluoro-propyl)-1H-pyrrole-2-carbonyl]-amino}-propionylamino)-hex-2(trans)-enoicAcid Ethyl Ester. (Compound 22)

[0410]

[0411] 5-(3,3,3-Trifluoro-propyl)-1H-pyrrole-2-carboxylic Acid Chloride

[0412] Method 5 General Experimental: 4,4,4-Trifluorobutyric acid (70.0mmol, 10.0 g) in CH₂Cl₂ (190 ml) was treated with oxalyl chloride (140mmol, 12.3 ml) and DMF (1 drop), then heated to reflux for 1 h. Solventand excess oxalyl chloride were removed from the volatile product bysimple distillation of the reaction mixture at atmospheric pressure toprovide crude 4,4,4-trifluorobutyric acid chloride (6.4 g). ¹H NMR(CDCl₃) δ 3.20 (2H, t, J=7.2), 2.65-2.45 (2H, m).

[0413] 4,4,4-Trifluorobutyric acid chloride (6.4 g from above) in CH₂Cl₂(80 ml) was treated with O,N-dimethylhydroxylamine hydrochloride (60.0mmol, 5.85 g). The mixture was cooled to 0° C., then treated withpyridine (160.0 mmol, 12.9 ml), then allowed to warm to room temperatureovernight. The mixture was diluted with CH₂Cl₂ (200 ml), then washedwith brine(2×50 ml). Solvent was removed from the volatile product bysimple distillation at atmospheric pressure to provide 20 g of4,4,4-trifluoro-N-methoxy-N-methyl butyramide, which may be used withoutfurther purification. ¹H NMR (CDCl₃) δ 3.70 (3H, s), 3.19 (3H, s),2.78-2.65 (2H, m), 2.57-2.40 (2H, m). Mg (92.0 mmol, 2.2 g) in THF (80ml), under an argon atmosphere, was treated with2-(2-bromoethyl)-[1,3]dioxolane (80 mmol, 9.4 ml), while keeping theinternal temperature below 35° C. with the aid of an ice bath. After theaddition was complete, the mixture was stirred for 2 h at roomtemperature, then cooled to −78° C. Crude4,4,4-trifluoro-N-methoxy-N-methyl butyramide (20 g, prepared above) inTHF (40 ml) was cooled to −78° C., then the freshly prepared Grignardreagent was transferred via cannula into the amide solution at −78° C.The resulting mixture was allowed to warm to room temperature, held atroom temperature overnight, then poured into saturated aqueous ammoniumchloride (200 ml). The mixture was extracted with ethyl acetate (3×75ml). The combined organics were washed with brine (2×75 ml) andconcentrated under reduced pressure to provide crude1-[1,3]dioxolan-2-yl-6,6,6-trifluoro-hexan-3-one (18 g) ¹H NMR (CDCl₃) δ4.91 (1H, t, J=4.1), 3.97-3.82 (4H, m), 2.70 (2H, t, J=7.3), 2.57 (2H,t, J=7.2), 2.49-2.34 (2H, m), 2.01 (2H, dt, J=7.3, 4.1).

[0414] Crude 1-[1,3]dioxolan-2-yl-6,6,6-trifluoro-hexan-3-one (18 g,prepared above) in 1:1 2N HCl-dioxane (80 ml) was heated to reflux for20 minutes, then neutralized with aqueous sodium bicarbonate (100 ml),then extracted with ethyl acetate (3×75 ml). The combined organics werewashed with brine (2×50 ml), then concentrated under reduced pressure toprovide crude 7,7,7-trifluoro-4-oxo-heptanal (10 g), which may be usedwithout further purification. ¹H NMR (CDCl₃) δ 9.80 (1H, s), 2.85-2.70(6H, m), 2.47-2.35 (2H, m).

[0415] Crude 7,7,7-trifluoro-4-oxo-heptanal (10 g, prepared above) inethanol (100 ml) was treated with ammonium chloride (400 mmol, 21 g),then heated to reflux for 1 h. The resulting solution was diluted withethyl acetate (300 ml) and washed with brine (2×50 ml). The organicswere concentrated under reduced pressure. Purification of the residue bysilica gel chromatography provided 1.3 g (21% overall from4,4,4-trifluorobutyric acid) of 2-(3,3,3-trifluoro-propyl)-1H-pyrrole.¹H NMR (CDCl₃) δ 7.98 (1H, br s), 6.71 (1H, dd, J=4.1, 2.6), 6.15 (1H,dd, J=5.9, 2.8), 5.99-5.94 (1H, m), 2.92-2.85 (2H, m), 2.52-2.35 (2H,m).

[0416] 2-(3,3,3-Trifluoro-propyl)-1H-pyrrole (8.15 mmol, 1.33 g) wasadded to a solution of trichloroacetyl chloride (8.15 mmol, 0.91 ml) indiethyl ether (10 ml). The resulting solution was held at roomtemperature for 1 h, then concentrated under reduced pressure. Theresulting solid was dissolved in 1:1 dioxane-water (20 ml), treated withlithium hydroxide (24.5 mmol, 0.59 g), and heated to reflux for 30minutes. After cooling to room temperature, the solution was acidifiedwith saturated aqueous citric acid (20 ml), then extracted with ethylacetate (2×50 ml). The combined organics were concentrated under reducedpressure. Purification of the resulting solid by silica gelchromatography provided 1.15 g (68%) of5-(3,3,3-trifluoropropyl)-1H-pyrrole-2-carboxylic acid. ¹H NMR (CDCl₃) δ9.33 (1H, br s), 6.99 (1H, dd, J=3.7, 2.5), 6.07 (1H, t, J=3.3),2.96-2.89 (2H, m), 2.55-2.39 (2H, m).

[0417] 5-(3,3,3-trifluoropropyl)-1H-pyrrole-2-carboxylic acid (5.55mmol, 1.15 g) in CH₂Cl₂ (10 ml) was treated with oxalyl chloride (16.7mmol, 1.5 ml), then DMF (1 drop). The solution was heated to reflux for1 h, then concentrated under reduced pressure to provide5-(3,3,3-trifluoropropyl)-1H-pyrrole-2-carboxylic acid chloride (1.04g). ¹H NMR (CDCl₃) δ 10.25 (1H, br s), 7.12 (1H, dd, J=4.0, 2.6), 6.12(1H, dd, J=3.8, 2.7), 3.05-2.88 (2H, m), 2.59-2.41 (2H, m).

[0418] The 5-(3,3,3-trifluoro-propyl)-1H-pyrrole-2-carboxylic acidchloride was coupled to Phe-Gln resin, and converted to the titlecompound according to the procedure described in Method 1 of Example 2.¹H NMR (CDCl₃) δ 10.30 (1H, br s), 7.41 (1H, d, J=8.5), 7.29-7.13 (4H,m), 6.61 (1H, dd, J=15.7, 5.3), 6.63 (1H, m), 5.93 (1H, br s), 5.53 (1H,dd, J=15.7, 1.3), 4.65 (1H, t, J=7.1), 4.53-4.42 (1H, m), 4.15 (2H, q,J=7.1), 3.05-3.00 (2H, m), 2.88-2.79 (2H, m), 2.45-2.30 (2H, m),2.20-2.10 (2H, m), 1.86-1.83 (1H, m), 1.75-1.66 (1H, m), 1.27 (3H, t,J=7.1). HRMS (MALDI) 559.2131 (MNa⁺, calcd. 559.2144).

Example 136-Carbamoyl-4S-{3-phenyl-2S-[(5-pyridin-3-yl-1H-pyrrole-2-carbonyl)-amino]-propionylamino}-hex-2(trans)-enoicAcid Ethyl Ester. (Compound 8)

[0419]

[0420] 5-Pyridin-3-yl-1H-pyrrole-2-carboxylic acid chloride was preparedaccording to the procedure described in Method 5 of Example 12, startingwith 3-pyridine carboxylic acid. This material was coupled to Phe-Glnresin, and converted to the title compound according to the proceduredescribed in Method 1 of Example 2. ¹H NMR (CD₃OD) δ 8.88 (1H, s), 8.41(1H, d, J=3.4), 8.11 (1H, d, J=7.9), 7.46 (1H, dd, J=8.0, 4.5),7.29-7.19 (5H, m), 6.90 (1H, d, J=3.9), 6.68 (1H, d, J=3.9), 6.66 (1H,dd, J=15.6, 5.6), 5.59 (1H, d, J=15.6), 4.71 (1H, t, J=7.7), 4.51-4.48(1H, m), 4.19 (2H, q, J=7.1), 3.11 (2H, t, J=8.5), 2.25-2.10 (2H, m),1.96-1.82 (1H, m), 1.75-1.60 (1H, m), 1.28 (3H, t, J=7.1). HRMS (MALDI)540.2217 (MNa⁺, calcd. 540.2223).

Example 144S-{2S-[(5-Benzo{1,3]dioxol-4-yl-1H-pyrrole-2-carbonyl)-amino-3-phenyl-propionylamino}-6-carbamoyl-hex-2(trans)-enoicAcid Ethyl Ester. (Compound 12)

[0421]

[0422] 5-Benzo[1,3]dioxol-4-yl-1H-pyrrole-2-carboxylic acid chloride wasprepared according to the procedure described in Method 5 of Example 12,starting with benzo[1,3]dioxole-4-carboxylic acid. This material wascoupled to Phe-Gln resin, and converted to the title compound accordingto the procedure described in Method 1 of Example 2. ¹H NMR (CD₃OD) δ7.32-7.24 (5H, m), 7.18 (1H, dd, J=7.1, 1.1), 6.95 (1H, d, J=3.9), 6.89(1H, t, J=5.1), 6.75 (1H, dd, J=7.7, 1.1), 6.70-6.63 (2H, m), 6.08 (2H,s), 5.58 (1H, d, J=15.3), 4.70 (1H, t, J7.7), 4.55-4.42 (1H, m), 4.18(2H, q, J=7.2), 3.10 (2H, t, J=8.0), 2.31 (2H, t, J=8.5), 1.96-1.82 (1H,m), 1.75-1.60 (1H, m), 1.27 (3H, t, J=7.1). HRMS (FAB) 583.2148 (MNa⁺,calcd. 583.2169).

Example 15 6-Carbamoyl-4S-(3-phenyl-2S-{[5-(3,3,3-trifluoro-1methyl-propyl)-1H-pyrrole-2-carbonyl]-amino}-propionylamino)-hex-2(trans)-enoicAcid Ethyl Ester. (Compound 13)

[0423]

[0424] 5-(3,3,3-trifluoro-1-methyl-propyl)-1H-pyrrole-2-carboxylic acidchloride was prepared according to the procedure described in Method 5of Example 12, starting with 4,4,4-trifluoro-2-methyl butyric acid. Thismaterial was coupled to Phe-Gin resin, and converted to the titlecompound according to the procedure described in Method 1 of Example 2.¹H NMR (CDCl₃) δ 10.00 (1H, br s), 7.32-7.16 (5H, m), 6.99 (1H, d,J=6.9), 6.77 (1H, br s), 6.67 (H, dd, J=15.7, 5.4), 6.62-6.58 (1H, m),6.20-6.01 (2H, m), 5.97 (1H, t, J=3.0), 5.66 (1H, d, J=15.9), 4.86-4.75(1H, m), 4.60-4.48 (1H, m), 4.17 (2H, q, J=7.1), 3.23-3.04 (3H, m),2.52-2.38 (1H, m), 2.22-2.12 (3H, m), 1.83-1.70 (1H, m), 1.23 (3H, d,J=7.0), 1.30 (3H, t, J=7.2). HRMS (MALDI) 573.2295 (MNa⁺, calcd.573.2301). Anal. (C₂₇H₃₃N₄O₅F₃.0.1 TFA) C, H, N.

Example 164S-(2S-{[5-(2-Bromo-phenyl)-1H-pyrrole-2-carbonyl]-amino}-3-phenyl-propionylamino)-6-carbamoyl-hex-2(trans)-enoicAcid Ethyl Ester. (Compound 14)

[0425]

[0426] 5-(2-bromo-phenyl)-1H-pyrrole-2-carboxylic acid chloride wasprepared according to the procedure described in Method 5 of Example 12,starting with 2-bromobenzoic acid. This material was coupled to Phe-Glnresin, and converted to the title compound according to the proceduredescribed in Method 1 of Example 2. ¹H NMR (CDCl₃) δ 10.30 (1H, br s),7.56 (1H, d, J=7.9), 7.41 (1H, dd, J=7.7, 1.5), 7.31-7.13 (7H, m), 7.08(1H, dt, J=7.8, 1.2), 7.01 (1H, d, J=8.6), 6.80-6.74 (1H, m), 6.64 (1H,dd, J=15.7, 5.3), 6.54-6.49 (1H, m), 6.26 (1H, br s), 6.14 (1H, br s),5.63 (1H, dd, J=15.7, 1.2), 4.83-4.72 (1H, m), 4.58-4.46 (1H, m), 4.37(2H, q, J=7.1), 3.20-3.02 (2H, m), 2.25-2.10 (2H, m), 1.96-1.82 (1H, m),1.75-1.60 (1H, m), 1.29 (3H, t, J=7.1). HRMS (MALDI) 617.1365 (MNa⁺,calcd. 617.1376). Anal. (C₂₉H₃₁N₄O₅Br.0.2 H₂O.0.3 TFA) C, H, N.

Example 176-Carbamoyl-4S-{3-phenyl-2S-[(5-pyridin-4-yl-1H-pyrrole-2-carbonyl)-amino]-propionylamino}-hex-2(trans)-enoicAcid Ethyl Ester. (Compound 15)

[0427]

[0428] 5-Pyridin-4-yl-1H-pyrrole-2-carboxylic acid chloride was preparedaccording to the procedure described in Method 5 of Example 12, startingwith 4-pyridine carboxylic acid. This material was coupled to Phe-Glnresin, and converted to the title compound according to the proceduredescribed in Method 1 of Example 2. ¹H NMR (CD₃OD) δ 8.50 (2H, d,J=6.7), 7.70 (2H, d, J=6.4), 7.30-7.19 (5H, m), 6.97 (1H, d, J=3.9),6.84 (1H, d, J=4.0), 6.66 (1H, dd, J=15.8, 5.6), 5.59 (1H, d, J=15.7),4.72 (1H, t, J=15.4), 4.60-4.40 (1H, m), 4.18 (2H, q, J=7.1), 3.17 (2H,t, J=7.9), 2.25-2.10 (2H, m), 1.96-1.82 (1H, m), 1.75-1.60 (1H, m), 1.28(3H, t, J=7.1). HRMS (MALDI) 540.2217 (MNa⁺, calcd. 540.2223).

Example 186-Carbamoyl-4S-(2S-{[5-(2-trifluoromethyl-phenyl)-1H-pyrrole-2-carbonyl]-amino}-pent-4-ynoylamino)-hex-2(trans)-enoicAcid Ethyl Ester. (Compound 16)

[0429]

[0430] Gln-resin was coupled with Fmoc-propargyl glycine, deprotected,then coupled to 5-(2-trifluoromethyl-phenyl)-1H-pyrrole-2-carboxylicacid chloride (prepared according to the procedure described in Method 6of Example 4), following Method 1 of Example 2. ¹H NMR (CDCl₃) δ 10.13(1H, s), 7.73 (1H, d, J=7.8), 7.60-7.40 (4H, m), 7.15 (1H, d, J=7.6),6.90-6.75 (2H, m), 6.38 (1H, s), 6.15 (2H, br s), 6.02 (1H, d, J=16.3),4.78-4.68 (1H, m), 4.68-4.55 (1H, m), 4.15 (2H, q, J=7.1), 2.80-2.20(4H, m), 2.12 (1H, s), 2.08-1.90 (1H, m), 1.90-1.75 (1H, m), 1.25 (3H,t, J=7.1). HRMS (MALDI) 555.1828 (MNa⁺, calcd. 555.1831). Anal.(C₂₆H₂₇F₃N₄O₅.0.8 H₂O).

Example 196-Carbamoyl-4S-(4-methyl-2S-{[5-(2-trifluoromethyl-phenyl)-1H-pyrrole-2-carbonyl]-amino}-pentanoylamino)-hex-2(trans)-enoicAcid Ethyl Ester. (Compound 17)

[0431]

[0432] Gln-resin was coupled with Fmoc-leucine, deprotected, thencoupled to 5-(2-trifluoromethyl-phenyl)-1H-pyrrole-2-carboxylic acidchloride (prepared according to the procedure described in Method 6 ofExample 4), following Method 1 of Example 2. ¹H NMR (CDCl₃) δ 10.06 (1H,s), 7.70 (1H, d, J=7.6), 7.60-7.38 (4H, m), 7.13 (1H, d, J=7.8)6.88-6.75 (2H, m), 6.36 (2H, br s), 6.19 (1H, br s), 5.91 (1H, d,J=15.5), 4.72-4.60 (1H, m), 4.60-4.45 (1H, m), 4.17 (2H, q, J=7.1),2.28-2.15 (2H, m), 2.00-1.85 (1H, m), 1.80-1.60 (4H, m), 1.27 (3H, t,J=7.1), 0.92 (3H, d, J=5.5), 0.88 (3H, d, J=5.5). HRMS (MALDI) 573.2292(MNa⁺, calcd. 573.2301). Anal. (C₂₇H₃₃N₄F₃O₅.0.2 H₂O.0.2 TFA) C, H, N.

Example 206-Carbamoyl-4S-(2S-{[5-(2-trifluoromethyl-phenyl)-1H-pyrrole-2-carbonyl]-amino}-pentanoylamino)-hex-2(trans)-enoicAcid Ethyl Ester. (Compound 18)

[0433]

[0434] Gln-resin was coupled with Fmoc-norvaline, deprotected, thencoupled to 5-(2-trifluoromethyl-phenyl)-1H-pyrrole-2-carboxylic acidchloride (prepared according to the procedure described in Method 6 ofExample 4), following Method 1 of Example 2. ¹H NMR (CDCl₃) δ 10.21 (1H,s), 7.69 (1H, d, J=7.7), 7.64 (1H, d, J=8.0), 7.55-7.33 (4H, m),6.88-6.75 (2H, m), 6.45-6.20 (3H, m), 5.91 (1H, d, J=15.7), 4.65-4.50(2H, m), 4.15 (2H, q, J=7.1), 2.25-2.15 (2H, m), 2.00-1.60 (4H, m),1.48-1.28 (2H, m), 1.25 (3H, t, J=7.1), 0.89 (3H, t, J=7.2). HRMS(MALDI) 559.2158 (MNa⁺, calcd. 559.2144).

Example 216-Carbamoyl-4S-(2S-{[5-(2-trifluoromethyl-phenyl)-1H-pyrrole-2-carbonyl]-amino}-hexanoylamino)-hex-2(trans)-enoicAcid Ethyl Ester. (Compound 19)

[0435]

[0436] Gln-resin was coupled with Fmoc-norleucine, deprotected, thencoupled to 5-(2-trifluoromethyl-phenyl)-1H-pyrrole-2-carboxylic acidchloride (prepared according to the procedure described in Method 6 ofExample 4), following Method 1 of Example 2. ¹H NMR (CDCl₃) δ 10.08 (1H,br s), 7.71 (1H, d, J=7.7), 7.56-7.38 (4H, m), 7.09 (1H, d, J=7.9),6.88-6.76 (2H, m), 6.37 (1H, s), 6.32 (1H, br s), 6.18 (1H, br s), 5.92(1H, d, J=15.0), 4.64-4.52 (2H, m), 4.16 (2H, q, J=7.1), 2.30-2.15 (2H,m), 2.00-1.65 (4H, m), 1.40-1.22 (7H, m), 0.87 (3H, t, J=6.3). HRMS(MALDI) 573.2307 (MNa⁺, calcd. 573.2301).

Example 226-Carbamoyl-4S-(2S-{[5-(2-trifluoromethyl-phenyl)-1H-pyrrole-2-carbonyl]-amino}-acetylamino)-hex-2(trans)-enoicAcid Ethyl Ester. (Compound 20)

[0437]

[0438] Gln-resin was coupled with Fmoc-glycine, deprotected, thencoupled to 5-(2-trifluoromethyl-phenyl)-1H-pyrrole-2-carboxylic acidchloride (prepared according to the procedure described in Method 6 ofExample 4), following Method 1 of Example 2. ¹H NMR (CD₃OD) δ 11.18 (1H,s), 7.79 (1H, d, J=7.8), 7.70-7.50 (3H, m), 6.92-6.88 (1H, m), 6.85 (1H,d, J=5.5), 6.32 (1H, m), 5.97 (1H, dd, J=15.7, 1.7), 4.64-4.54 (1H, m),4.17 (2H, q, J=7.1), 4.02 (2H, d, J=2.4), 2.35-2.27 (2H, m), 2.06-1.94(1H, m), 1.90-1.75 (1H, m), 1.27 (3H, t, J=7.1). HRMS (MALDI) 495.1874(MNa⁺, calcd. 495.1855).

Example 236-Carbamoyl-4S-(2S-{[5-(3-methyl-isoxazol-5-yl)-1H-pyrrole-2-carbonyl]-amino}-3-phenyl-propionylamino)-hex-2(trans)-enoicAcid Ethyl Ester. (Compound 21)

[0439]

[0440] 3-Methyl-5-(1H-pyrrol-2-yl)-isoxazole (Sundberg, et al., J. Org.Chem., 1985, 50, 425) was converted to5-(3-methyl-isoxazol-5-yl)-1H-pyrrole-2-carboxylic acid chlorideaccording to the procedure described in Method 5 of Example 12, thencoupled to Phe-Gln resin following Method 1 of Example 2, then cleavedfrom resin to provide the title compound. ¹H NMR (CD₃OD) δ 7.31-7.19(6H, m), 6.93 (1H, d, J=3.9), 6.67 (1H, d, J=4.0), 6.64 (1H, dd, J=15.3,5.7), 6.49 (1H, s), 5.57 (1H, dd, J=15.8, 0.9), 4.69 (1H, t, J=15.6),4.55-4.46 (1H, m), 4.18 (2H, q, J=7.1), 3.12 (2H, t, J=7.6), 2.31 (2H,q, J=8.0), 2.05-1.94 (1H, m), 1.83-1.74 (1H, m), 1.28 (3H, t, J=7.1).HRMS 544.2163 (MNa⁺, calcd. 544.2172).

Example 246-Carbamoyl-4S-(2S-{[5-(2-trifluoromethyl-phenyl)-1H-pyrrole-2-carbonyl]-amino}-butyrlamino)-hex-2(trans)-enoicAcid Ethyl Ester. (Compound 23)

[0441]

[0442] Gln-resin was coupled with Fmoc-aminobutyric acid, deprotected,then coupled to 5-(2-trifluoromethyl-phenyl)-1H-pyrrole-2-carboxylicacid chloride (prepared according to the procedure described in Method 6of Example 4), following Method 1 of Example 2. ¹H NMR (CDCl₃) δ 10.06(1H, br s), 7.72 (1H, d, J=7.7), 7.63-7.37 (4H, m), 7.02 (1H, d, J=7.5),6.88-6.76 (2H, m), 6.37 (1H, s), 6.28 (1H, br s), 6.18 (1H, br s), 5.92(1H, d, J=15.8), 4.68-4.45 (2H, m), 4.16 (2H, q, J=7.1), 2.34-2.22 (2H,m), 2.04-1.65 (4H, m), 1.26 (3H, t, J=7.1), 0.95 (3H, t, J=7.1). HRMS(MALDI) 545.2002 (MNa⁺, calcd. 545.1988).

Example 25 5-Naphthalen-1-yl-1H-pyrrole-2-carboxylic acid-{1S-[2-oxo-dihydrofuran-3-ylidine)-1-(2-oxo-pyrrolidin-3S-methyl)-ethylcarbamoyl]-2S-(4-fluoro-phenyl-ethyl)}-amide. (Compound 26)

[0443]

[0444] Method 2 General Experimental: Boc-protected3S-[2S-amino-3-(2-oxo-dihydro-furan-3-ylidine)-propyl]-pyrrolidin-2-one,prepared by a method analogous to that described in Tian, et al., U.S.Provisional Patent Application No. 60/150,358, filed Aug. 24, 1999 andalso Baldwin et al., J. Org. Chem., 1971, 36, 1441, (3.40 mmol, 1.10 g)in CH₂Cl₂ (10 ml) was treated with HCl (17.0 mmol, 4.3 ml of 4M indioxane), and held at room temperature for 1 h, then concentrated underreduced pressure. The product was diluted with DMF (10 ml), treated withBoc-4-fluoro-phenylalanine (3.40 mmol, 0.96 g), DIEA (10.2 mmol, 1.8ml), and HATU (3.40 mmol, 1.29 g), then held at room temperature for 1h. The resulting solution was diluted with in ethyl acetate (75 ml),washed with brine (3×20 ml), then concentrated under reduced pressure.The residue was purified by silica gel chromatography to provide 0.84 g(51%) of2-(4-fluorophenyl)-1S-[2-(2-oxodihydrofuran-3-ylidine)-1-(2-oxo-pyrrolidin-3S-ylmethyl)-ethylcarbamoyl]-ethyl-carbamic acid t-butyl ester. ¹H NMR (CDCl₃) δ 7.82 (1H,br s), 7.15-7.07 (2H, m), 6.96 (2H, t, J=8.7), 6.32 (1H, d, J=8.2), 6.00(1H, s), 5.22 (1H, d, J=7.8), 4.55-4.32 (4H, m), 3.40-3.28 (2H, m),3.28-3.10 (1H, m), 3.05-2.95 (2H, m), 2.95-2.83 (1H, m), 2.50-2.20 (2H,m), 2.10-1.90 (1H, m), 1.90-1.70 (2H, m), 1.58-1.46 (1H, m), 1.39 (9H,s).

[0445]2-(4-Fluorophenyl)-1S-[2-(2-oxodihydrofuran-3-ylidine)-1-(2-oxo-pyrrolidin-3S-ylmethyl)-ethylcarbamoyl]-ethyl-carbamic acid t-butyl ester (0.96 mmol, 0.47 g) inCH₂Cl₂ (5 ml) was treated with HCl (4.8 mmol, 1.2 ml of 4M in dioxane),and held 1 h, then concentrated under reduced pressure. The product wasdiluted with CH₂Cl₂ (5 ml) and collidine (2.89 mmol, 0.38 ml), andtreated with 5-naphthalene-1-yl-1H-pyrrole-2-carboxylic acid chloride(prepared according to the procedure described in Method 4 of Example 2,starting with 1-naphthalene boronic acid, 0.96 mmol, 0.25 g), then heldat room temperature for 1 h. The resulting solution was diluted withethyl acetate (75 ml), washed with saturated aqueous sodium bicarbonate(2×20 ml) and brine (2×20 ml), then concentrated under reduced pressure.Purification of the residue by silica gel chromatography gave 0.17 g(29%) of product. ¹H NMR (CDCl₃) δ 10.05 (1H, s), 8.27-8.13 (2H, m)7.92-7.80 (2H, m), 7.57-7.45 (4H, m), 7.20-7.11 (2H, m), 7.05-6.95 (3H,m), 6.73 (1H, d, J=9.6), 6.51 (1H, dd, J=3.7, 2.6), 6.32 (1H, DT, J=8.5,2.9), 5.36 (1H, br s), 5.15-5.05 (1H, m), 4.46-4.32 (3H, m), 3.42-3.18(4H, m), 3.02-2.82 (2H, m), 2.36-2.25 (1H, m), 1.90-1.65 (3H, m),1.60-1.48 (1H, m). HRMS (FAB) 741.1466 (MCs⁺, calcd. 741.1489).

Example 26 5-(2-Oxo-pyrrolidin-3S-yl)-4S-{3-phenyl-2S-[(1H-pyrrole-2-carbonyl)-amino]-propionylamino}-pent-2(trans)-enoic AcidEthyl Ester. (Compound 24)

[0446]

[0447] 4S-Amino-5-(2-oxo-pyrrolidin-3S-yl)-pent-2(trans)-enoic acidethyl ester was coupled to Boc-phenylalanine, then deprotected andcoupled to pyrrole-2-carboxylic acid chloride, following Method 2 ofExample 25. ¹H NMR (CD₃OD) δ 7.23-7.08 (5H, m), 6.82 (1H, dd, J=2.5,1.4), 6.71 (1H, dd, J=3.8, 1.4), 6.58 (1H, dd, J=10.2, 5.5), 6.13 (1H,dd, J=3.8, 2.5), 5.57 (1H, dd, J=15.8, 1.6), 4.74 (1H, t, J=6.8),4.47-4.36 (1H, m), 4.10 (2H, q, J=7.1), 3.11-2.94 (2H, m), 2.27-2.13(2H, m), 1.84-1.57 (1H, m), 1.49-1.38 (1H, m), 1.21 (3H, t, J=7.1). HRMS(FAB) 467.2299 (MH⁺, calcd. 467.2294).

Example 274S-{2S-[(5-Naphthalen-1-yl-1H-pyrrole-2-carbonyl)-amino]-3-phenyl-propionylamino}-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicAcid Ethyl Ester. (Compound 25)

[0448]

[0449] 4S-Amino-5-(2-oxo-pyrrolidin-3S-yl)-pent-2(trans)-enoic acidethyl ester was coupled to Boc-phenylalanine, then deprotected andcoupled to 5-naphthalen-1-yl-pyrrole-2-carboxylic acid chloride(prepared according to the procedure described in Method 4 of Example 2,starting with 1-naphthyl boronic acid) following Method 2 of Example 25.¹H NMR (CDCl₃) δ 10.28 (1H, s), 8.21 (1H, d, J=9.0), 7.83-7.80 (3H, m),7.57-7.44 (4H, m), 7.34-7.18 (5H, m), 7.02-6.96 (1H, m), 6.74 (1H, d,J=9.1), 6.67 (1H, dd, J=10.2, 5.4), 6.52-6.46 (1H, m), 5.75 (1H, d,J=15.6), 5.18 (1H, br s), 5.13-5.03 (1H, m), 4.47-4.36 (1H, m), 4.17(2H, q, J=7.1), 3.41-3.31 (1H, m), 3.17-3.07 (2H, m), 3.06-2.97 (1H, m),2.30-2.18 (1H, m), 2.05-1.92 (1H, m), 1.80-1.58 (2H, m), 1.55-1.45 (1H,m), 1.27 (3H, t, J=7.1). HRMS (FAB) 593.2750 (MH⁺, calcd. 593.2764).

Example 28 5-Phenyl-1H-pyrrole-2-carboxylicacid-{2S-(4-fluorophenyl)-1S-[1-(2-oxo-dihydrofuran-3-ylidinemethyl)-1-(2-oxo-pyrrolidin-3S-methyl)-ethylcarbamoyl]-2S-phenyl-ethyl}-amide. (Compound 27)

[0450]

[0451]2-(4-Fluorophenyl)-1S-[2-(2-oxodihydrofuran-3-ylidine)-1-(2-oxo-pyrrolidin-3S-ylmethyl)-ethylcarbamoyl]-ethyl-carbamic acid t-butyl ester (prepared as described inMethod 2 of Example 25) was deprotected, then coupled to5-phenyl-1H-pyrrole-2-carboxylic acid chloride (prepared according tothe procedure described in Method 5 of Example 12, starting with benzoicacid), following Method 2 of Example 25. ¹H NMR (CDCl₃) δ 10.48 (1H, s),7.56 (2H, d, J=7.3), 7.36 (2H, t, J=7.7), 7.26-7.19 (1H, m), 7.14-7.06(2H, m), 6.93 (2H, t, J=8.7), 6.85-6.81 (1H, m), 6.51-6.47 (1H, m), 6.28(1H, dt, J=8.8, 3.9), 4.83 (1H, t, J=5.2), 4.50-4.39 (1H, m), 4.34 (2H,t, J=7.6), 3.30-3.27 (2H, m), 3.18-2.90 (3H, m), 2.91-2.76 (1H, m),2.36-2.13 (2H, m), 1.98-1.85 (1H, m), 1.80-1.66 (1H, m), 1.53-1.43 (1H,m). HRMS (FAB) 581.2161 (MNa⁺, calcd. 581.2176).

Example 295-(2-Oxo-pyrrolidin-3S-yl)-4S-(3-phenyl-2S-{[5-(2-trifluoromethyl-phenyl)-1H-pyrrole-2-carbonyl]-amino}-propionylamino)-pent-2(trans)-enoicAcid Ethyl Ester. (Compound 28)

[0452]

[0453] 4S-Amino-5-(2-oxo-pyrrolidin-3S-yl)-pent-2(trans)-enoic acidethyl ester was coupled to Boc-phenylalanine, then deprotected andcoupled to 5-(2-trifluoromethyl-phenyl)-1H-pyrrole-2-carboxylic acidchloride (prepared according to the procedure described in Method 6 ofExample 4, starting with 2-trifluoromethyl benzaldehyde) followingMethod 2 of Example 25. ¹H NMR (CDCl₃) δ 10.00 (1H, s), 7.75-7.65 (2H,m), 7.57-7.35 (3H, m), 7.30-7.13 (4H, m), 6.98 (1H, d, J=8.8), 6.84 (1H,br s), 6.65 (1H, dd, J=10.2, 5.4), 6.38 (1H, br s), 6.15 (1H, br s),5.72 (1H, d, J=14.7), 5.10-4.98 (1H, m), 4.52-4.40 (1H, m), 4.17 (2H, q,J=7.1), 3.28-3.15 (3H, m), 3.00 (1H, dd, J=13.4, 7.0), 2.32-2.20 (1H,m), 2.18-2.05 (1H, m), 1.88-1.60 (2H, m), 1.58-1.48 (1H, m), 1.27 (3H,t, J=7.1). HRMS (MALDI) 611.2475 (MH⁺, calcd. 611.2481). Anal.(C₃₂H₃₃N₄O₅F₃.1.0 H₂O) C, H, N.

Example 305-(2-Oxo-pyrrolidin-3S-yl)-4S-(2S-{[5-(2-trifluoromethyl-phenyl)-1H-pyrrole-2-carbonyl]-amino}-pent-4-ynoylamino)-pent-2(trans)-enoicAcid Ethyl Ester. (Compound 29)

[0454]

[0455] 4S-Amino-5-(2-oxo-pyrrolidin-3S-yl)-pent-2(trans)-enoic acidethyl ester was coupled to Boc-propargyl glycine, then deprotected andcoupled to 5-(2-trifluoromethyl-phenyl)-1H-pyrrole-2-carboxylic acidchloride (prepared according to the procedure described in Method 6 ofExample 4, starting with 2-trifluoromethyl benzaldehyde) followingMethod 2 of Example 25. ¹H NMR (CDCl₃) δ 10.13 (1H, s), 8.10 (1H, d,J=7.4), 7.73 (1H, d, J=7.8), 7.59-7.40 (3H, m), 7.19 (1H, d, J=8.4),6.88 (1H, dd, J=3.8, 2.5), 6.83 (1H, dd, J=15.7, 5.0), 6.43-6.35 (1H,m), 6.03 (1H, dd, J=15.7, 1.6), 4.92-4.83 (1H, m), 4.65-4.54 (1H, m),4.15 (2H, q, J=7.1), 3.32-3.23 (2H, m), 2.87-2.61 (2H, m), 2.50-2.22(2H, m), 2.06 (1H, t, J=2.5), 2.00-1.92 (1H, m), 1.86-1.58 (2H, m), 1.25(3H, t, J=7.1). HRMS (MALDI) 581.1992 (MNa⁺, calcd. 581.1988). Anal.(C₂₈H₂₉N₄O₅F₃.0.5 H₂O) C, H, N.

Example 31 6-Carbamoyl-4S-(2S{methyl-[5-(2-trifluoromethyl-phenyl)-1H-pyrrole-2-carbonyl]-amino}-3-3-phenyl-propionylamino)-hex-2(trans)-enoicAcid Ethyl Ester. (Compound 41)

[0456]

[0457] Gln-resin was coupled with Fmoc-N-methyl-phenylalanine, accordingto the procedure described in Method 1 of Example 2, then deprotectedand coupled with 5-(2-trifluoromethyl-phenyl)-1H-pyrrole-2-carboxylicacid (prepared according to the procedure described in Method 6 ofExample 4), according to the procedure described in Method 1 of Example2. ¹H NMR (CD₃OD) δ 7.90-7.50 (4H, m), 7.35-7.15 (5H, m), 6.88 (1H, dd,J=15.8, 5.4), 6.60-6.58 (1H, m), 6.38-6.32 (1H, m), 5.98 (1H, dd,J=15.8, 1.6), 5.32-5.20 (1H, m), 4.65-4.50 (1H, m), 4.25-4.10 (2H, m),4.18 (2H, q, J=7.1), 3.50-3.10 (5H, m), 2.33-2.20 (2H, m), 2.03-1.72(2H, m), 1.23 (3H, t, J=7.1). HRMS (MALDI) 621.2301 (MNa⁺, calcd.621.2301).

Example 32 4S-[2(R,S)-Benzyl-4-oxo-4-(1H-pyrrol-2-yl)-butyrylamino-5-(2-oxo-pyrrolidin-3S-yl)-pent-2(trans)-enoicAcid Ethyl Ester

[0458]

[0459] 2(R,S)-Benzyl-4-oxo-4-(1 H-pyrrol-2-yl)-butryric Acid

[0460] Method 7 General Experimental: Pyrrole-2-carboxylic acid (27.0mmol, 3.00 g) in CH₂Cl₂ (100 ml) was treated with oxalyl chloride (54.0mmol, 4.70 ml) and DMF (1 drop), then heated to reflux for 1 h, thenconcentrated under reduced pressure. The residue was diluted with CH₂Cl₂(100 ml) and pyridine (6.50 ml), and treated withO,N-dimethyl-hydroxylamine hydrochloride (27.0 mmol, 2.65 g), then heldat room temperature overnight. The resulting solution was diluted withethyl acetate (250 ml), washed with 10% aqueous citric acid (2×30 ml),saturated aqueous sodium bicarbonate (2×30 ml), then brine (2×30 ml).The organics were concentrated under reduced pressure. Purification ofthe residue by silica gel chromatography provided 3.42 g (82%) of1H-pyrrole-2-carboxylic acid methoxy-methyl amide. ¹H NMR (CDCl₃) δ6.90-6.80 (1H, m), 6.79-6.60 (1H, m), 6.18 (1H, dd, J=3.7, 1.3), 3.81(3H, s), 3.01 (3H, s).

[0461] 1H-pyrrole-2-carboxylic acid methoxy-methyl amide (22.2 mmol,3.42 g) in THF (100 ml) was cooled to −78° C., and treated with methyllithium-lithium bromide complex (44.4 mmol, 29.6 ml of 1.5 M in Et₂O).The solution was held at −78° C. for 20 minutes, allowed to warm to 0°C., and held 30 minutes, then poured into saturated aqueous ammoniumchloride (300 ml). The mixture was extracted with ethyl acetate (3×150ml). The combined organic extracts were washed with brine (3×50 ml) andconcentrated under reduced pressure. The residue was purified by silicagel chromatography to provide 2.28 g (94%) of1-(1H-pyrrol-2-yl)-ethanone. ¹H NMR (CDCl₃) δ 7.03 (1H, dt, J=2.7, 1.3),6.91 (1H, ddd, J=3.8, 2.4, 1.3), 6.30-6.26 (1H, m), 2.44 (3H, s).

[0462] 1-(1H-pyrrol-2-yl)-ethanone (2.67 mmol, 0.29 g) in CH₂Cl₂ (10 ml)and Et₃N (13.3 mmol, 1.90 ml) was cooled to 0° C. and treated withtrimethylsilyl trifluoromethanesulfonate (5.34 mmol, 1.00 ml). Thesolution was held at 0° C. for 30 minutes, then diluted with ethylacetate (75 ml) and washed with saturated aqueous sodium bicarbonate(2×20 ml) then brine (30 ml). The solution was concentrated underreduced pressure to provide crude2-[1-(trimethyl-silanyloxy)-vinyl]-1H-pyrrole. ¹H NMR (CDCl₃) δ 6.77(1H, dd, J=2.7, 1.6), 6.34 (1H, dd, J=3.2, 1.6), 6.15 (1H, t, J=2.8),4.56 (1H, d, J=1.0), 4.31 (1H, d, J=1.0), 0.45 (9H, s), 0.25 (9H, s).

[0463] Crude 2-[1-(trimethyl-silanyloxy)-vinyl]-1H-pyrrole was dilutedwith CH₂Cl₂ (10 ml), cooled to 0° C., and treated withN-bromosuccinimide (1.94 mmol, 0.35 g). The resulting mixture was put ina −20° C. freezer overnight. After warming to room temperature, themixture was diluted with ethyl acetate (75 ml), washed with saturatedaqueous sodium bicarbonate (2×20 ml), brine (2×20 ml), and the organicsconcentrated under reduced pressure. Purification of the residue bysilica gel chromatography provided 0.29 g (80%) of2-bromo-1-(1H-pyrrol-2-yl)-ethanone. ¹H NMR (CDCl₃) δ 7.12 (1H, dt,J=2.7, 1.3), 7.02 (1H, ddd, J=3.8, 2.4, 1.3), 6.36-6.31 (1H, m), 4.27(2H, s).

[0464] 2-Bromo-1-(1H-pyrrol-2-yl)-ethanone (1.00 mmol, 0.19 g) in DME (3ml) was treated with NaI (1.00 mmol, 0.15 g), and stirred vigorously for30 minutes. A solution of diethyl malonate (1.50 mmol, 0.2 ml), NaH(1.00 mmol, 40 mg of 60% in oil), and DME (3 ml) was added to thebromide-NaI mixture, and held at room temperature overnight. Saturatedaqueous ammonium chloride (10 ml) was added, then the mixture wasextracted with ethyl acetate (2×25 ml). The combined organic extractswashed with brine (25 ml), then concentrated under reduced pressure.Purification of the residue by silica gel chromatography provided 0.21 g(79%) of 2-(1H-pyrrole-2-carbonyl)-malonic acid diethyl ester. ¹H NMR(CDCl₃) δ 9.76 (1H, s), 7.04 (1H, dt, J=2.7, 1.3), 7.00 (1H, ddd, J=3.8,2.4, 1.3), 6.30-6.26 (1H, m), 4.21 (4H, m), 4.02 (1H, t, J=7.3), 3.45(2H, d, J=7.3), 1.25 (6H, t, J=7.1).

[0465] 2-(1H-Pyrrole-2-carbonyl)-malonic acid diethyl ester (0.79 mmol,0.21 g) in DME (3 ml) was treated with lithium bis-trimethylsilylamide(0.79 mmol, 133 mg). The resulting solution was held at room temperaturefor 30 minutes, then treated with benzyl bromide (0.79 mmol, 0.10 ml).The resulting solution was held at room temperature overnight, thendiluted with ethyl acetate (30 ml), and washed with saturated ammoniumchloride (10 ml), followed by brine (20 ml). The organics wereconcentrated under reduced pressure and the residue was purified bysilica gel chromatography to provide 0.23 g (84%) of2-benzyl-2-(1H-pyrrole-2-carbonyl)-malonic acid diethyl ester. ¹H NMR(CDCl₃) δ 10.01 (1H, s), 7.25-7.17 (4H, m), 7.14 (1H, dt, J=2.7, 1.3),7.03-6.98 (1H, m), 6.86 (1H, ddd, J=3.8, 2.4, 1.3), 6.29-6.25 (1H, m),4.22 (4H, q, J=7.1), 3.47 (2H, s), 3.39 (2H, s), 1.25 (6H, t, J=1.7).

[0466] 2-Benzyl-2-(1H-pyrrole-2-carbonyl)-malonic acid diethyl ester(0.66 mmol, 0.23 g) in 1:1 dioxane-water (10 ml) was treated withlithium hydroxide (1.31 mmol, 31 mg), then heated to reflux for 30minutes. The solution was treated with saturated aqueous citric acid (20ml), extracted with ethyl acetate (30 ml). The organic extract waswashed with brine (15 ml) then concentrated under reduced pressure. Theresidue was purified by silica gel chromatography to provide 0.11 g(64%) of 2(R,S)-benzyl-4-oxo-4-(1H-pyrrol-2-yl)-butyric acid. ¹H NMR(CDCl₃) δ 7.18-7.04 (5H, m), 6.92 (1H, dd, J=2.4, 1.4), 6.80 (1H, dd,J=3.8, 1.3), 6.08 (1H, dd, J=3.8, 2.5), 3.20-2.85 (3H, m), 2.80-2.67(2H, m).

[0467] Method 3 General Experimental:2(R,S)-Benzyl-4-oxo-4-(1H-pyrrol-2-yl)-butyric acid (0.42 mmol, 0.11 g,prepared according to the procedure described in Example 7),4S-amino-5-(2-oxo-pyrrolidin-3S-yl)-pent-2(trans)-enoic acid ethyl esterhydrochloride (0.42 mmol, 0.11 g), and DIEA (1.26 mmol, 0.22 ml) in DMF(2 ml) were treated with HATU (0.42 mmol, 0.16 g), then held at roomtemperature overnight. The resulting solution was diluted with ethylacetate (30 ml), washed with brine (2×15 ml). The organics wereconcentrated under reduced pressure and the residue was purified bysilica gel chromatography to provide 0.14 g (75%) of product. Thediastereomers were separated by preparative reverse phase HPLC(CH₃CN-water gradient).

[0468] 2R-Benzyl diastereomer (Compound 30): ¹H NMR (CDCl₃) δ 11.05 (1H,s), 7.40 (1H, d, J=8.0), 7.32-7.15 (5H), 7.05 (1H, ddd, J=3.8, 2.4,1.3), 7.00-6.96 (2H, m), 6.52 (1H, dd, J=15.7, 5.0), 6.27-6.23 (1H, m),5.32 (1H, dd, J=15.7, 1.6), 4.44-4.32 (1H, m), 4.14 (2H, q, J=7.1), 3.53(1H, dd, J=14.4, 10.9), 3.34-3.02 (4H, m), 2.85 (1H, dd, J=13.1, 4.9),2.57 (1H, dd, J=14.5, 3.1), 2.20-2.08 (1H, m), 1.98-1.84 (1H, m),1.72-1.60 (1H, m), 1.60-1.41 (1H, m), 1.40-1.28 (1H, m), 1.28 (3H, t,J=7.1). HRMS (FAB) 466.2234 (MH⁺, calcd. 466.2342).

Example 332-(R,S)-(4-Fluorobenzyl)-4-oxo-N-[2-(2-oxo-dihydro-furan-3-ylidine)-1S-(2-oxo-pyrrolidin-3S-ylmethyl)-ethyl]-4-(5-phenyl-1H-pyrrol-2-yl)-butyramide.(Compound 31)

[0469]

[0470]2-(R,S)-(4-Fluorobenzyl)-4-oxo-4-(5-phenyl-1H-pyrrol-2-yl)-butyric acidwas prepared according to the procedure described in Example 7, startingwith 5-phenyl-1H-pyrrole-2-carboxylic acid (prepared according to theprocedure described in Example 4, starting with phenylboronic acid).This material was coupled to3S-[2S-amino-3-(2-oxo-dihydro-furan-3-ylidene)-propyl]pyrrolidin-2-onehydrochloride according to the procedure described in Method 3 ofExample 31, to provide the title compound as a 1:1 mixture of 2R-2Sdiastereomers. ¹H NMR (CDCl₃) δ 10.24 (0.5 H, br s), 9.90 (0.5 H, br s),7.70-6.85 (11 H, m), 6.61-6.54 (1H, m), 6.37-6.27 (1H, m), 6.27-6.18(1H, m), 4.50-4.13 (3H, m), 3.42-2.60 (9H, m), 2.25-1.20 (5H, m). HRMS(FAB) 580.2228 (MNa⁺, calcd. 580.2224).

Example 342-(R,S)-(4-Fluorobenzyl)-4-(5-naphthalen-1-yl-1H-pyrrol-2-yl)-4-oxo-N-[2-(2-oxo-dihydro-furan-3-ylidine)-1S-(2-oxo-pyrrolidin-3S-ylmethyl)-ethyl]-butyramide

[0471]

[0472]2-(R,S)-(4-Fluorobenzyl)-4-oxo-4-(5-naphthalen-1-yl-1H-pyrrol-2-yl)-butyricacid was prepared according to the procedure described in Example 7,starting with 5-naphthalen-1-yl-1H-pyrrole-2-carboxylic acid (preparedaccording to the procedure described in Example 4, starting with1-naphthylboronic acid). This material was coupled to3S-[2S-amino-3-(2-oxo-dihydro-furan-3-ylidene)-propyl]pyrrolidin-2-onehydrochloride according to the procedure described in Method 3 ofExample 31, to provide the title compound as a 1:1 mixture of 2R-2Sdiastereomers. The diastereomers were separated by preparative reversephase chromatography (acetonitrile-H₂O gradient).

[0473] 2R-(4-Fluorobenzyl) diastereomer (Compound 33): ¹H NMR (CDCl₃) δ10.48 (1H, s), 8.07 (1H, d, J=8.2), 7.87 (1H, d, J=7.8), 7.82 (1H, d,J=8.1), 7.70 (1H, d, J=5.6), 7.55-7.30 (4H, m), 7.15-7.02 (3H, m),6.98-6.89 (2H, m), 6.55 (1H, br s), 6.48 (1H, br s), 6.22 (1H, d,J=8.5), 4.40-4.28 (3H, m), 3.80-1.30 (14H, m). HRMS (FAB) 740.1512(MCs⁺, calcd. 740.1537).

[0474] 2S-(4-Fluorobenzyl) diastereomer (Compound 32): ¹H NMR (CDCl₃) δ9.81 (1H, br s), 8.04 (1H, d, J=8.6), 7.85-7.68 (3H, m), 7.52-7.35 (4H,m), 7.20-6.85 (5H, m), 6.50-6.25 (3H, m), 4.35-4.18 (3H, m), 3.28-2.60(9H, m), 2.20-1.85 (2H, m), 1.70-1.55 (2H, m), 1.40-1.22 (1H, m). HRMS(FAB) 740.1512 (MCs⁺, calcd. 740.1537).

Example 352-(R,S)-(4-Fluorobenzyl)-4-oxo-N-[2-(2-oxo-dihydro-furan-3-ylidine)-1S-(2-oxo-pyrrolidin-3S-ylmethyl)-ethyl]-4-(1H-pyrrol-2-yl)-butyramide. (Compound 34)

[0475]

[0476] 2-(R,S)-(4-Fluorobenzyl)-4-oxo-4-(1 H-pyrrol-2-yl)-butyric acid)was prepared according to the procedure described in Example 7, startingwith 2-pyrrolecarboxylic acid. This material was coupled to3S-[2S-amino-3-(2-oxo-dihydro-furan-3-ylidene)-propyl]pyrrolidin-2-onehydrochloride according to the procedure described in Method 3 ofExample 31, to provide the title compound as a 1:1 mixture of 2R-2Sdiastereomers. ¹H NMR (CDCl₃) δ 10.62 (0.5H, br s), 10.12 (0.5H, br s),7.83 (0.5H, d, J=7.7), 7.62 (0.5H, d, J=7.1), 7.20-6.82 (6H, m),6.65-6.20 (3H, m), 4.50-4.20 (3H, m), 3.45-2.60 (9H, m), 2.25-1.90 (3H,m), 1.68-1.50 (1H, m), 1.42-1.20 (1H, m). HRMS (FAB) 504.1932 (MNa⁺,calcd. 504.1911).

Example 365-(2-Oxo-pyrrolidine-3S-yl)-4S-(2R-{2-oxo-2-[5-(2-trifluoromethyl-phenyl)-1H-pyrrol-2-yl]-ethyl}-pent-4-ynoylamino-pent-2(trans)-enoicAcid Ethyl Ester. (Compound 36)

[0477]

[0478] Method 8 General Experimental: 4-Pentynoic acid (60.1 mmol, 5.90g) in THF (140 ml) was cooled to −78° C., then treated with Et₃N (69.1mmol, 9.60 ml), followed by pivaloyl chloride (61.9 mmol, 7.6 ml). Theresulting mixture was allowed to warm to 0° C., held 30 minutes, thenrecooled to −78° C. A solution of 4S-isopropyl-2-oxazolidinone (60.1mmol, 7.76 g) in THF (140 ml) was cooled to −78° C. and treated withbutyllithium (61.9 mmol, 24.8 ml of 2.5M in hexanes), held at −78° C.for 30 minutes, then transferred via cannula at −78° C. into the4-pentynoic acid-pivaloyl chloride solution. The mixture was held at−78° C. for 1 h, then warmed to 0° C. and held 30 minutes, then pouredinto saturated aqueous ammonium chloride (200 ml). The solution wasextracted with ethyl acetate (3×150 ml). The combined organic extractswere washed with brine (2×50 ml), then concentrated under reducedpressure to give 12.8 g of 4S-isopropyl-3-pent-4-ynoyl-oxazolidin-2-one,which may be used without further purification. ¹H NMR (CDCl₃) δ4.44-4.37 (1H, m), 4.29-4.15 (2H, m), 3.23-3.01 (2H, m), 2.50 (2H, dt,J=7.1, 2.6), 2.39-2.27 (1H, m), 1.93 (1H, t, J=2.6), 0.87 (3H, d,J=7.0), 0.82 (3H, d, J=6.9).

[0479] 4S-Isopropyl-3-pent-4-ynoyl-oxazolidin-2-one (7.50 mmol, 2.11 g)in THF (25 ml) was cooled to −78° C. and treated with a solution oflithium bis(trimethylsilyl)amide (8.25 mmol, 1.38 g) in THF (5 ml). Theresulting solution was allowed to warm to 0° C., held 15 minutes, thenre-cooled to −78° C., then treated with t-butyl bromoacetate (22.5 mmol,3.3 ml). The resulting solution was held at −78° C. for 15 minutes, thenwarmed to 0° C. and held for 2 h. The solution was then poured intosaturated aqueous ammonium acetate (30 ml), then extracted with ethylacetate (2×50 ml). The combined organic extracts were washed with brine(2×15 ml), then concentrated under reduced pressure. The residue waspurified by silica gel chromatography to provide 1.23 g (43%) of3R-(4S-isopropyl-2-oxo-oxazolidine-3-carbonyl)-hex-5-ynoic acid t-butylester. ¹H NMR (CDCl₃) δ 4.46-4.39 (1H, m), 4.35-4.16 (3H, m), 2.87 (1H,dd, J=16.7, 9.8), 2.59-2.27 (4H, m), 2.00 (1H, t, J=2.6), 1.39 (9H, s),0.90 (3H, d, J=3.9), 0.87 (3H, d, J=4.0).

[0480] 3R-(4S-Isopropyl-2-oxo-oxazolidine-3-carbonyl)-hex-5-ynoic acidt-butyl ester (10.12 mmol, 3.27 g) in THF (100 ml) and H₂O (50 ml) wascooled to 0° C. and treated with lithium hydroxide hydrate (20.2 mmol,0.85 g), followed by H₂O₂ (41.5 mmol, 4.7 ml of 30% aqueous). Theresulting solution was held at 0° C. for 1 h, then allowed to warm toroom temperature and held 3 h. The solution was then cooled to 0° C.,and quenched with saturated aqueous sodium bisulfite (30 ml). Thesolution was acidified with saturated aqueous citric acid (30 ml), andextracted with ethyl acetate (75 ml). The organic extract was washedwith brine (30 ml), then concentrated under reduced pressure. Theresidue was purified by silica gel chromatography to provide2R-prop-2-ynyl-succinic acid-4-t-butyl ester. This material was treatedwith diazomethane (30 mmol, generated from N-nitroso-N-methyl urea),then concentrated under reduced pressure to give 1.95 g of2R-prop-2-ynyl-succinic acid 4-t-butyl ester 1-methyl ester. Thismaterial was treated with 20% TFA —CH₂Cl₂ (30 ml), held 30 min, thenconcentrated under reduced pressure to give 1.47 g (85%) of2R-prop-2-ynyl-succinic acid-1-methyl ester. ¹H NMR (CDCl₃) δ 10.12 (1H,br s), 3.08-2.50 (5H, m), 3.73 (3H, s), 2.05 (1H, t, J=2.7).

[0481] 2R-Prop-2-ynyl-succinic acid-1-methyl ester (8.63 mmol, 1.47 g)in CH₂Cl₂ (30 ml) was treated with oxalyl chloride (17.3 mmol, 1.50 ml)and DMF (1 drop), then heated to reflux for 30 minutes, thenconcentrated under reduced pressure. The residue was diluted with CH₂Cl₂(30 ml), and pyridine (43.2 mmol, 3.5 ml), then treated withdimethylamine hydrochloride (25.9 mmol, 2.11 g), and held at roomtemperature overnight. The resulting mixture was diluted with ethylacetate (150 ml) and washed with brine (3×30 ml). The organics wereconcentrated under reduced pressure. Purification of the residue bysilica gel chromatography provided 0.83 g (49%) of2R-dimethylcarbamoylmethyl-pent-4-ynoic acid methyl ester. ¹H NMR(CDCl₃) δ 3.69 (3H, s), 3.18-2.52 (I 1H, m), 2.00 (1H, t, J=2.7).

[0482] 2R-Dimethylcarbamoylmethyl-pent-4-ynoic acid methyl ester (4.20mmol, 0.89 g) was cooled to 0° C. and treated with POCl₃ (4.2 mmol, 0.40ml). The mixture was allowed to warm to room temperature, and held for 1h then diluted with ethylene dichloride (10 ml), and re-cooled to 0° C.2-(2-Trifluoromethyl-phenyl)-1H-pyrrole (4.2 mmol, 0.89 g, preparedaccording to the procedure described in Example 6) in ethylenedichloride (10 ml) was added, and the mixture was allowed to warm toroom temperature, then heated to reflux for 2 h. The mixture was thenallowed to cool to room temperature, then treated with saturated aqueoussodium acetate (10 ml), and heated to reflux for 15 minutes. Thesolution was then carefully neutralized with saturated aqueous sodiumbicarbonate (20 ml), and extracted with ethyl acetate (75 ml). Theorganic extract was washed with brine (25 ml), then concentrated underreduced pressure. The residue was purified by silica gel chromatographyto provide 1.11 g (72%) of2R-(2-oxo-2-[5-(2-trifluoromethyl-phenyl)-1H-pyrrol-2-yl]-ethyl)-pent-4-ynoicacid methyl ester. ¹H NMR (CDCl₃) δ 9.50 (1H, br s), 7.78 (1H, d,J=7.4), 7.64-7.46 (3H, m), 7.02 (1H, dd, J=3.9, 2.5), 6.45 (1H, t,J=3.0), 3.72 (3H, s), 3.45-3.14 (3H, m), 2.62 (1H, d, J=2.7), 2.59 (1H,d, J=2.6), 2.04 (1H, t, J=2.7). This material was diluted with 1:1H₂O-dioxane (40 ml), and treated with lithium hydroxide hydrate (9.18mmol, 0.38 g), then heated to reflux for 30 minutes. The solution wasacidified with saturated aqueous citric acid (20 ml), extracted withethyl acetate (3×30 ml). The combined organic extracts were washed withbrine (3×20 ml), then concentrated under reduced pressure. The residuewas purified by silica gel chromatography to provide 0.67 g (60%) of2R-(2-oxo-2-[5-(2-trifluoromethyl-phenyl)-1H-pyrrol-2-yl]-ethyl)-pent-4-ynoicacid.

[0483]2R-(2-oxo-2-[5-(2-trifluoromethyl-phenyl)-1H-pyrrol-2-yl]-ethyl)-pent-4-ynoicacid was coupled with4S-amino-5-(2-oxo-pyrrolidin-3S-yl)-pent-2(trans)-enoic acid ethyl esterhydrochloride according to the procedure described in Method 3 ofExample 31. ¹H NMR (CD₃OD) δ 10.31 (1H, br s), 7.73 (1H, d, J=7.9),7.61-7.42 (3H, m), 6.99 (1H, d, J=4.0), 6.82 (1H, dd, J=15.7, 4.6), 6.39(1H, d, J=3.8), 6.04 (1H, dd, J=15.7, 1.6), 4.64-4.54 (1H, m), 4.13 (2H,q, J=7.1), 3.38-2.92 (5H, m), 2.62-2.38 (3H, m), 2.25-2.12 (1H, m), 2.10(1H, t, J=2.6), 2.05-1.89 (1H, m), 1.75-1.60 (1H, m), 1.60-1.48 (1H, m),1.24 (3H, t, J=7.1). HRMS (MALDI) 558.2221 (MH⁺, calcd. 558.2216). Anal.(C₂₉H₃₀N₃O₅F₃.0.3 H₂O) C, H, N.

Example 374S-{2R-Benzyl-4-oxo-4-[5-(2-trifluoromethyl-phenyl)-1H-pyrrol-2-yl]-butyrylamino}-5-(2-oxo-pyrrolidin-3S-yl)-pent-2(trans)-enoicAcid Ethyl Ester. (Compound 35)

[0484]

[0485] 2R-Benzyl-N,N-dimethyl-succinamic acid was prepared according tothe procedure described in Example 8, starting with hydrocinnamic acid.This material was reacted with 2-(2-trifluoromethyl-phenyl)-1H-pyrrole(prepared according to the procedure described in Example 6), thendemethylated to give2R-benzyl-4-oxo-4-[5-(2-trifluoromethyl-phenyl)-1H-pyrrol-2-yl]-butyricacid (all following Method 8). This material was coupled to4S-amino-5-(2-oxo-pyrrolidin-3S-yl)-pent-2(trans)-enoic acid ethyl esterhydrochloride according to the procedure described in Method 3 ofExample 31. ¹H NMR (CDCl₃) δ 10.01 (1H, br s), 7.72 (1H, d, J=7.7),7.55-7.40 (3H, m), 7.34-7.16 (5H, m), 6.98 (1H, dd, J=3.9, 2.4), 6.90(1H, d, J=7.4), 6.62 (1H, dd, J=15.7, 5.1), 6.41 (1H, t, J=3.2), 6.13(1H, br s), 5.49 (1H, dd, J=15.7, 1.6), 4.56-4.44 (1H, m), 4.16 (2H, q,J=7.1), 3.39 (1H, dd, J=16.1, 9.5), 3.25-2.96 (4H, m), 2.83-2.69 (2H,m), 2.42-2.28 (1H, m), 2.22-2.08 (1H, m), 1.94-1.78 (1H, m), 1.72-1.55(1H, m), 1.52-1.40 (1H, m), 1.30 (3H, t, J=7.1). HRMS (MALDI) 610.2532(MH⁺, calcd. 610.2529). Anal. (C₃₃H₃₄F₃N₃O₅) C, H, N.

Example 384S-{2R-Ethyl-4-oxo-4-[5-(2-trifluoromethyl-phenyl)-1H-pyrrol-2-yl]-butyrylamino}-5-(2-oxo-pyrrolidin-3S-yl)-pent-2(trans)-enoicAcid Ethyl Ester. (Compound 37)

[0486]

[0487] 2R-Ethyl-N,N-dimethyl-succinamic acid methyl ester was preparedaccording to the procedure described in Example 8, starting with butyricacid. This was reacted with 2-(2-trifluoromethyl-phenyl)-1H-pyrrole(prepared according to the procedure described in Example 6), thendemethylated to give2R-ethyl-4-oxo-4-[5-(2-trifluoromethyl-phenyl)-1H-pyrrol-2-yl]-butyricacid (all following Method 8). This material was then coupled to4S-amino-5-(2-oxo-pyrrolidin-3S-yl)-pent-2(trans)-enoic acid ethyl esterhydrochloride according to the procedure described in Method 3 ofExample 31. ¹H NMR (CDCl₃) δ 10.13 (1H, br s), 7.76 (1H, d, J=7.8),7.62-7.46 (3H, m), 7.01 (1H, d, J=3.9), 6.84 (1H, dd, J=15.7, 5.2), 6.42(1H, d, J=3.9), 5.93 (1H, dd, J=15.3, 1.6), 4.70-4.60 (1H, m), 4.17 (2H,q, J=7.1), 3.36-3.15 (3H, m), 2.86-2.70 (2H, m), 2.58-2.53 (1H, m),2.33-2.23 (1H, m), 2.05-1.94 (1H, m), 1.83-1.74 (2H, m), 1.61-1.51 (2H,m), 1.27 (3H, t, J=7.1), 1.01 (3H, t, J=7.3). HRMS (MALDI) 548.2363(MH⁺, calcd. 548.2372). Anal. (C₂₈H₃₂N₃O₅F₃.0.7 H₂O) C, H, N.

Example 394S-(2R-{2-[5-(2-Chloro-phenyl)-1H-pyrrol-2-yl]-2-oxo-ethyl}-pent-4-ynoylamino)-5-(2-oxo-pyrrolidin-3S-yl)-pent-2(trans)-enoicAcid Ethyl Ester. (Compound 38)

[0488]

[0489] 2R-Dimethylcarbamoylmethyl-pent-4-ynoic acid methyl ester wasprepared according to the procedure described in Example 8, startingwith 4-pentynoic acid. This material was reacted with2-(2-chloro-phenyl)-1H-pyrrole (prepared according to the proceduredescribed in Example 6, starting with 2-chlorobenzaldehyde). Thisproduct was demethylated to give2R-{2-[5-(2-chloro-phenyl)-1H-pyrrol-2-yl]-2-oxo-ethyl}-pent-4-ynoicacid (all following Method 8), then coupled to4S-amino-5-(2-oxo-pyrrolidin-3S-yl)-pent-2(trans)-enoic acid ethyl esterhydrochloride according to the procedure described in Method 3 ofExample 31. ¹H NMR (CDCl₃) δ 10.58 (1H, br s), 7.65 (1H, d, J=7.4), 7.56(1H, dd, J=7.6, 1.8), 7.46 (1H, dd, J=7.7, 1.4), 7.37-7.23 (2H, m), 7.07(1H, dd, J=4.0, 2.4), 6.83 (1H, dd, J=15.6, 4.7), 6.68 (1H, dd, J=4.0,2.6), 6.28 (1H, br s), 6.05 (1H, dd, J=15.7, 1.6), 4.58-4.46 (1H, m),4.15 (2H, q, J=7.1), 3.38 (1H, dd, J=15.3, 9.8), 3.15 (1H, t, J=9.1),3.10-2.95 (2H, m), 2.87 (1H, dd, J=15.3, 3.7), 2.63 (1H, ddd, J=16.8,7.3, 2.6), 2.47 (1H, ddd, J=16.8, 7.5, 2.6), 2.28-2.15 (1H, m), 2.10(1H, t, J=2.5), 2.06-1.88 (2H, m), 1.73-1.50 (2H, m), 1.26 (3H, t,J=7.1). HRMS (MALDI) 546.1750 (MNa⁺, calcd. 546.1722). Anal.(C₂₈H₃₀N₃O₅Cl.0.6 H₂O) C, H, N.

Example 405-(2-Oxo-pyrrolidin-3S-yl)-4S-{2R-[2-oxo-2-(5-o-tolyl-1H-pyrrol-2-yl)-ethyl]-pent-4-ynoylamino}-pent-2(trans)-enoicAcid Ethyl Ester. (Compound 39)

[0490]

[0491] 2R-Dimethylcarbamoylmethyl-pent-4-ynoic acid methyl ester wasprepared according to the procedure described in Example 8, startingwith 4-pentynoic acid. This material was reacted with2-(o-tolyl)-1H-pyrrole (prepared according to the procedure described inExample 5, starting with o-toluic acid). This product was demethylatedto give 2R-[2-oxo-2-(5-o-tolyl-1H-pyrrol-2-yl)-ethyl]-pent-4-ynoic acid(all following Method 8), then coupled to4S-amino-5-(2-oxo-pyrrolidin-3S-yl)-pent-2(trans)-enoic acid ethyl esterhydrochloride according to the procedure described in Method 3 ofExample 31. ¹H NMR (CDCl₃) δ 10.65 (1H, br s), 7.50 (1H, d, J=7.6),7.43-7.36 (1H, m), 7.30-7.21 (3H, m), 7.10-7.04 (1H, m), 6.82 (1H, dd,J=15.6, 5.4), 6.47 (1H, br s), 6.39-6.33 (1H, m), 6.04 (1H, d, J=15.6),4.59-4.48 (1H, m), 4.15 (2H, q, J=7.1), 3.39 (1H, dd, J=15.4, 10.4),3.12-2.95 (2H, m), 2.95-2.77 (2H, m), 2.68-2.55 (1H, m), 2.51-2.38 (1H,m), 2.40 (3H, s), 2.36-2.25 (1H, m), 2.12 (1H, br s), 2.03-1.90 (1H, m),1.66-1.43 (2H, m), 1.26 (3H, t, J=7.1). HRMS (MALDI) 504.2497 (MH⁺,calcd. 504.2498). Anal. (C₂₉H₃₃N₃O₅.0.7 H₂O) C, H, N.

Example 414S-{2R-Benzyl-4-oxo-[5-(2-trifluoromethyl-phenyl)-1H-pyrrol-2-yl]-butyrylamino}-6-carbamoyl-hex-2(trans)-enoicAcid Ethyl Ester. (Compound 40)

[0492]

[0493] 2R-Benzyl-N,N-dimethyl-succinamic acid (prepared according to theprocedure described in Example 8, starting with hydrocinnamic acid) wasreacted with 2-(2-trifluoromethyl-phenyl)-1H-pyrrole (prepared accordingto the procedure described in Example 6), then demethylated to give2R-benzyl-4-oxo-4-[5-(2-trifluoromethyl-phenyl)-1H-pyrrol-2-yl]-butyricacid (all following Method 8), then coupled to Gln-resin, followingMethod 1. ¹H NMR (CD₃OD) δ 7.70 (1H, d, J=7.3), 7.58-7.41 (3H, m),7.25-7.11 (5H, m), 6.95 (1H, d, J=4.0), 6.53 (1H, dd, J=15.8, 5.1), 6.35(1H, d, J=3.9) 5.38 (1H, dd, J=15.8, 1.7), 4.47-4.38 (1H, m), 4.12 (2H,q, J=7.1), 3.31 (1H, m), 3.08-2.70 (4H, m), 2.13 (2H, t, J=7.9),1.92-1.78 (1H, m), 1.63-1.50 (1H, m), 1.25 (3H, t, J=7.1). HRMS (MALDI)606.2194 (MNa⁺, calcd. 606.2192).

Example 424S-(4-oxo-pentanoylamino)-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoic AcidEthyl Ester (Compound 43)

[0494]

[0495] 4S-Amino-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoic acid ethyl ester(0.15 mmol, 35 mg) in DMF (1.5 ml) was treated with diisopropylethylamine (0.30 mmol, 0.05 ml), 4-oxopentanoic acid (0.15 mmol, 27 mg), andHATU (0.15 mmol, 57 mg), and held at room temperature for 1 h. Thesolution was washed with brine (10 ml), and extracted with EtOAc (2×10ml) and concentrated under reduced pressure to provide 40 mg of crudeproduct. Purification by preparative reverse phase chromatography(CH₃CN—H₂O) provided 28 mg (48%) of the title product. ¹H NMR (CDCl₃) δ7.28 (1H, s), 6.83 (1H, dd, J=15.7, 5.2), 6.03 (1H, s), 5.92 (1H, dd,J=15.7, 1.5), 4.65-4.50 (1H, m), 4.17 (2H, q, J=7.1), 3.40-3.30 (2H, m),2.92-2.65 (2H, m), 2.60-2.35 (4H, m), 2.17 (3H, m), 2.05-1.90 (1H, m),1.90-1.72 (1H, m), 1.70-1.60 (1H, m), 1.27 (3H, t, J=7.1). MS (ES) 347(MNa⁺), 323 (M−H)⁻.

Example 434S-(4-oxo-4-phenyl-butyrylamino)-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicAcid Ethyl Ester. (Compound 44)

[0496]

[0497] The title compound was prepared according to the method ofExample 42, using 4-oxo-4-phenylbutyric acid. ¹H NMR (CDCl₃) δ 8.10-7.95(2H, m), 7.60-7.53 (1H, m), 7.50-7.42 (2H, m), 6.86 (1H, dd, J=15.6,5.7), 5.97 (1H, d, J=15.6), 5.73 (1H, s), 4.65-4.61 (1H, m), 4.19 (2H,q, J=7.1), 3.50-3.20 (4H, m), 2.73-2.64 (2H, m), 2.62-2.35 (2H, m),2.08-1.95 (1H, m), 1.92-1.65 (2H, m), 1.28 (3H, t, J=7.1). MS (ES) 387(MH⁺), 409 (MNa⁺).

Example 444-S-(4-Naphthalen-1-yl-4-oxo-butyrylamino)-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicAcid Ethyl Ester. (Compound 45)

[0498]

[0499] The title compound was prepared according to the method ofExample 42, using as starting material gamma-oxo-1-naphthalene butyricacid. ¹H NMR (CDCl₃) δ 8.57 (1H, d, J=8.6), 7.99-7.37 (7H, m), 6.88 (1H,dd, J=15.6, 5.4), 6.05 (1H, s), 6.01 (1H, d, J=15.6), 4.65-4.64 (1H, m),4.17 (2H, q, J=7.2), 3.57-3.27 (4H, m), 2.86-2.39 (4H, m), 2.09-1.66(3H, m), 1.25 (3H, t, J=7.2). MS (FAB) 437.2068 (MH⁺, calcd. 437.2076).

Example 454S-[2-(3-Chloro-phenylcarbamoyl)-acetylamino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicAcid Ethyl Ester. (Compound 46)

[0500]

[0501] The title compound was prepared according to the method ofExample 42, using as starting material N-(3-chloro-phenyl)-malonamicacid. ¹H NMR (CDCl₃) δ 9.89 (1H, s), 8.69 (1H, d, J=6.1), 7.69 (1H, s),7.41-7.36 (1H, m), 7.22 (1H, t, J=8.1), 7.09-7.03 (1H, m), 6.84 (1H, dd,J=15.7, 5.7), 5.96 (1H, d, J=15.6), 5.97 (1H, s), 4.59-4.48 (1H, m),4.18 (2H, q, J=7.1), 3.43-3.34 (4H, m), 2.57-2.37 (2H, m), 2.06-1.80(2H, m), 1.74 (1H, dt, J=14.5, 4.3), 1.27 (3H, t, J=7.1). MS (FAB)422.1494 (MH⁺, calcd 422.1483), 444 (MNa⁺).

Example 46 Preparation of Ethyl-3-{(Indole-2-carboxylicacid)-L-(4-F-Phe)-L-[(S)-Pyrrol-Ala]}-E-Propenoate. (Compound 42)

[0502]

[0503] In this example, the following shorthand naming system employingamino acid abbreviations is used to identify some intermediates andfinal products. When naming compounds, italicized amino acidabbreviations represent modifications at the C-terminus of that residuewhere the following apply: (1) acrylic acid esters are reported as “E”(trans) propenoates; (2) substituted 3-methylene-dihydrofuran-2-ones arereported as “E” (trans) 2-(a-vinyl-g-butyrolactones); and (3)5-vinylisoxazoles are reported as “E” (trans) propenisoxazoles.

Ethyl-3-{Boc-L-(4-F-Phe)-L-[(N-2,4-Dimethoxybenzyl)-(S)-Pyrrol-Ala]}-E-Propenoate

[0504]

[0505] A solution of HCl in 1,4-dioxane (4.0 M, 12 ml) was added to asolution ofethyl-3-{Boc-L-[(N-2,4-dimethoxybenzyl)-(S)-Pyrrol-Ala]}-E-propenoate,prepared according to the procedure described in Dragovich, et al., J.Med. Chem. 1999, 42, 1213, (0.432 g, 0.906 mmol, 1 equiv) in the samesolvent (12 ml). After stirring 1.5 h at 23° C., the solvent wasconcentrated under reduced pressure to give the crude amine salt. Thismaterial was dissolved in DMF (7 ml) and cooled to 0° C.Boc-L-(4-F-Phe)—OH (0.308 g, 1.09 mmol, 1.2 equiv),N,N-diisopropylethylamine (0.474 ml, 2.72 mmol, 3 equiv) and HATU (0.379g, 0.997 mmol, 1.1 equiv) were added sequentially and the reactionmixture was allowed to warm to 23° C. After 1.5 h, the mixture wasdiluted with MTBE (200 ml), and washed with 5% KHSO₄ and brine (20 mleach), dried over MgSO₄ and concentrated. The residue was purified byflash column chromatography (60% EtOAc in hexanes) to provideethyl-3-{Boc-L-(4-F-Phe)-L-[(N-2,4-dimethoxybenzyl)-(S)-Pyrrol-Ala]}-E-propenoate(0.447 g, 77%) as a white foam: R_(f)=0.34 (60% EtOAc in hexanes); IR(cm⁻¹) 3258, 1705, 1666; ¹H NMR (CDCl₃) δ 1.28 (t, 3H, J=7.2), 1.45 (s,9H), 1.51-1.66 (m, 2H), 1.78-1.90 (m, 1H), 2.06-2.23 (m, 2H), 2.99 (dd,1H, J=13.7, 6.2), 3.11 (dd, 1H, J=13.7, 5.3), 3.17-3.23 (m, 2H), 3.80(s, 3H), 3.81 (s, 3H), 4.18 (q, 2H, J=7.2), 4.35 (s, 2H), 4.38-4.51 (m,2H), 5.29-5.37 (m, 1H), 5.76 (d, 1H, J=15.8), 6.43-6.47 (m, 2H), 6.72(dd, 1H, J=15.8, 5.3), 6.83-6.91 (m, 2H), 7.09-7.17 (m, 3H), 7.92 (br,1H); Anal. (C₃₄H₄₄FN₃O₈) C, H, N.

Preparation of IntermediateEthyl-3-{Boc-L-(4-F-Phe)-L-[(S)-Pyrrol-Ala]}-E-Propenoate

[0506]

[0507] 2,3-Dicholoro-5,6-dicyano-1,4-benzoquinone (0.14 g, 0.62 mmol, 1equiv) was added to a solution ofethyl-3-{Boc-L-(4-F-Phe)-L-[(N-2,4-dimethoxybenzyl)-(S)-pyrrol-Ala]}-E-propenoate(0.39 g, 0.53 mmol, 1 equiv) in CHCl₃ (25 ml) and water (2.5 ml) and thereaction mixture was heated to reflux at 60° C. After 2 h, an additionalequivalent of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone was added to themixture. After 2 h, one more equivalent of2,3-dichloro-5,6-dicyano-1,4-benzoquinone was added to the mixture. Thereaction mixture was diluted with EtOAc (150 ml) and washed sequentiallywith NaHCO₃ (100 ml) and brine (100 ml). The organic layers were driedover Na₂SO₄, concentrated, and the residue was purified by flash columnchromatography (2% CH₃OH in CH₂Cl₂) to affordethyl-3-{Boc-L-(4-F-Phe)-L-[(S)-pyrrol-Ala]}-E-propenoate (0.205 g, 79%)as a white solid: R_(f)=0.18 (5% CH₃OH in CH₂Cl₂); IR (cm⁻¹) 3281, 2981,1690; ¹H NMR (CDCl₃) δ 1.27-1.31 (t, 3H, J=7.2), 1.42 (s, 9H), 1.57-1.64(m, 1H), 1.75-1.94 (m, 2H), 2.23-2.36 (m, 2H), 3.01-3.05 (m, 2H),3.29-3.34 (m, 2H), 4.18 (q, 2H, J=7.2), 4.42-4.50 (m, 2H), 5.23 (m, 1H),5.69-5.79 (m, 2H), 6.69-6.74 (m, 1H), 6.94-7.00 (m, 1H), 7.14-7.18 (m,2H), 7.43 (m, 1H); Anal. Calcd for C₂₅H₃₄FN₃O₆.0.5H₂O C, 59.99; H, 7.05;N, 8.39. Found C, 59.63; H, 7.05; N, 8.14.

Ethyl-3-{(Indole-2-carboxylicacid)-L-(4-F-Phe)-L-[(S)-Pyrrol-Ala]}-E-Propenoate

[0508] A solution of HCl in 1,4-dioxane (4.0 M, 2 ml) was added toethyl-3-{Boc-L-(4-F-Phe)-L-[(S)-pyrrol-Ala]}-E-propenoate (0.19 g, 0.39mmol, 1 equiv) in 2 ml of 1,4-dioxane at 23° C. After 2 h, the volatileswere removed under reduced pressure and CH₂Cl₂ (3 ml) and Et₃N (1 ml)were added sequentially to the residue. In a separate flask,N-hydroxysuccinimide (0.075 g, 0.65 mmol, 1.1 equiv) and1,3-dicyclohexylcarbodiimide (0.13 g, 0.64 mmol, 1.1 equiv) were addedto a solution of indole-2-carboxylic acid (0.99 g, 0.62 mmol, 1 equiv)in CH₂Cl₂ (3 ml) and DMF (1 ml) and stirred at 23° C. for 3 h. Thissolution was then filtered and added to the original reaction mixturedescribed above. The resulting solution was stirred at 23° C. for 16 h.then was partitioned between water (25 ml) and CH₂Cl₂ (2×20 ml). Thecombined organic layers were dried over Na₂SO₄, concentrated, and theresidue was purified by flash column chromatography (1 to 5% CH₃OH inCH₂Cl₂) to afford ethyl-3-{(indole-2-carboxylicacid)-L-(4-F-Phe)-L-[(S)-pyrrol-Ala]}-E-propenoate (0.145 g, 70%) as awhite powder: R_(f)=0.44 (10% CH₃OH in CH₂Cl₂); IR (cm⁻¹) 3277, 1636,1547; ¹H NMR (DMSO-d₆) δ 1.28 (t, 3H, J=7.2), 1.51-1.59 (m, 1H),1.66-1.73 (m, 1H), 1.89-1.96 (m, 1H), 2.10-2.18 (m, 1H), 2.39-2.42 (m,1H), 3.09-3.17 (m, 4H), 4.18 (q, 2H, J=7.5), 4.62 (m, 1H), 4.75-4.77 (m,1H), 5.71-5.82 (m, 1H), 6.87 (dd, 1H, J=4.2, 15.9), 7.07-7.17 (m, 3H),7.21-7.26 (m, 3H), 7.42-7.47 (m, 3H), 7.66-7.70 (m, 2H), 8.45 (d, 1H,J=8.7), 8.72 (d, 1H, J=7.8); Anal. Calcd for C₂₉H₃₁FN₄O₅.0.35 H₂O: C,64.40; H, 5.91; N, 10.36. Found C, 64.12; H, 5.91; N, 10.14.

[0509] Results of tests conducted using exemplary compounds of theinvention are described below.

BIOCHEMICAL AND BIOLOGICAL EVALUATION Inhibition of Rhinovirus 3CProtease

[0510] Stock solutions (50 mM, in DMSO) of various compounds wereprepared; dilutions were in the same solvent. Recombinant rhinovirus 3Cproteases (see Birch et al., “Purification of recombinant humanrhinovirus 14 3C protease expressed in Escherichia coli,” Protein Expr.Pur. (1995), vol. 6(5), 609-618) from serotypes 14, 16, and 2 wereprepared by the following standard chromatographic procedures: (1) ionexchange using Q Sepharose Fast Flow from Pharmacia; (2) affinitychromatography using Affi-Gel Blue from Biorad; and (3) sizing usingSephadex G-100 from Pharmacia. Each assay sample contained 2% DMSO, 50mM tris pH 7.6, 1 mM EDTA, a test compound at the indicatedconcentration, approximately 1 μM substrate, and 50-100 nM protease. Thek_(obs/I) values were obtained from reactions initiated by addition ofenzyme rather than substrate. RVP activity was measured in thefluorescence resonance energy transfer assay. The substrate was(N-terminal) DABCYL-(Gly-Arg-Ala-Val-Phe-Gln-Gly-Pro-Val-Gly)-EDANS. Inthe uncleaved peptide, the EDANS fluorescence was quenched by theproximal DABCYL moiety. When the peptide was cleaved, the quenching wasrelieved, and activity was measured as an increase in fluorescencesignal. Data were analyzed using standard non-linear fitting programs(Enzfit), and are shown in the table below. The tabulated data in thecolumn designated k_(obs)/[I] were measured from progress curves inenzyme start experiments.

Antirhinoviral H1-HeLa Cell Culture Assay

[0511] In this cell protection assay, the ability of compounds toprotect cells against HRV infection was measured by the XTT dyereduction method, which is described in Weislow et al., J. Natl. CancerInst. (1989), vol. 81, 577-586. H1-HeLa cells were infected with HRV-14at a multiplicity of infection (m.o.i.) of 0.13 (virus particles/cell)or mock-infected with medium only. Infected or mock-infected cells wereresuspended at 8×10⁵ cells per ml, and incubated with appropriateconcentrations of the compounds to be tested. Two days later, XTT/PMSwas added to test plates and the amount of formazan produced wasquantified spectrophotometrically at 450/650 nm. The EC₅₀ value wascalculated as the concentration of compound that increased thepercentage of formazan production in compound-treated, virus-infectedcells to 50% of that produced by compound-free, mock-infected cells. The50% cytotoxic dose (CC₅₀) was calculated as the concentration ofcompound that decreased the percentage of formazan produced incompound-treated, mock-infected cells to 50% of that produced bycompound-free, mock-infected cells. The therapeutic index (TI) wascalculated by dividing the CC₅₀ value by the EC₅₀ value.

[0512] All strains of human rhinovirus (HRV) for use in this assay werepurchased from American Type Culture Collection (ATCC), except for HRVserotype-14 (produced from the infectious cDNA clone constructed by Dr.Robert Rueckert, Institute for Molecular Virology, University ofWisconsin, Madison, Wis.). HRV stocks were propagated and viral assayswere performed in H1-HeLa cells (ATCC). Cells were grown in minimalessential medium with 10% fetal bovine serum, available from LifeTechnologies (Gaithersburg, Md.). Test results for the HRV assay areshown in the table below.

Anticoxsackieviral Cell Culture Assay

[0513] Coxsackievirus types A-21 (CAV-21) and B3 (CVB3) were purchasedfrom American Type Culture Collection (ATCC, Rockville, Md.). Virusstocks were propagated and antiviral assays were performed in H1-HeLacells (ATCC). Cells were grown in minimal essential medium with 10%fetal bovine serum (Life Technologies, Gaithersburg, Md.). The abilityof the compounds of this invention to protect cells against eitherCAV-21 or CVB3 infection was measured by the XTT dye reduction method.This method is described in Weislow et al., J. Natl. Cancer Inst.(1989), vol. 81, 577-586. H1-HeLa cells were infected with CAV-21 orCVB3 at a multiplicity of infection (m.o.i.) of 0.025 or 0.075,respectively, or mock-infected with medium only. H1-HeLa cells wereplated at 4×10⁴ cells per well in a 96-well plate and incubated withappropriate concentrations of the test compound. One day (CVB3) or twodays (CAV-21) later, XTT/PMS was added to test plates and the amount offormazan produced was quantified spectrophotometrically at 450/650 nm.The EC₅₀ was calculated as the concentration of compound that increasedthe formazan production in compound-treated, virus-infected cells to 50%of that produced by compound-free, uninfected cells. The 50% cytotoxicdose (CC₅₀) was calculated as the concentration of compound thatdecreased formazan production in compound-treated, uninfected cells to50% of that produced in compound-free, uninfected cells. The therapeuticindex (TI) was calculated by dividing the CC₅₀ by the EC₅₀.

Anti-Echoviral and Anti-Enteroviral Cell Culture Assays

[0514] Echovirus type 11 (ECHO 11) was purchased from ATCC (Rockville,Md.). Virus stocks were propagated and antiviral assays were performedin MRC-5 cells (ATCC). Cells were grown in minimal essential medium with10% fetal bovine serum (Life Technologies, Gaithersburg, Md.). Theability of the compounds of this invention to protect cells against ECHO11 infection was measured by the XTT dye reduction method (Weislow etal., J. Natl. Cancer Inst. (1989), vol. 81, 577-586). MRC-5 cells wereinfected with ECHO 11 at an m.o.i. of 0.003 or 0.004, respectively, ormock-infected with medium only. Infected or uninfected cells were addedat 1×10⁴ cells per well and incubated with appropriate concentrations ofcompound. Four days later, XTT/PMS was added to test plates, and theamount of formazan produced was quantified spectrophotometrically at450/650 nm. The EC₅₀ was calculated as the concentration of compoundthat increased the formazan production in compound-treated,virus-infected cells to 50% of that produced by compound-free,uninfected cells. The 50% cytotoxic dose (CC₅₀) was calculated as theconcentration of compound that decreased formazan production incompound-treated, uninfected cells to 50% of that produced incompound-free, uninfected cells. The therapeutic index (TI) wascalculated by dividing the CC₅₀ by the EC₅₀. Activity of the compoundsagainst enterovirus type 70 (EV 70) may be measured by the same assay asdescribed above in this section. Enterovirus type 70 (EV 70) may beobtained from the American Type Culture Collection ATCC (Rockville,Md.).

[0515] Antiviral data obtained for the test compounds are shown in thetable below. The designation “ND” indicates that a value was notdetermined for that compound, and the designation “NA” means notapplicable. TABLE Virus K_(obs)/I Compound # Serotype (M⁻¹s⁻¹) EC₅₀ (μM)CC₅₀ (μM) 1 HRV-14 20300 0.202 >10 2 HRV-14 32400 0.064 >10 3 HRV-1430800 0.109 >10 4 HRV-14 5860 ND ND 5 HRV-14 12700 1.098 >10 6 HRV-142130 1.425 >10 7 HRV-14 5200 0.3 >10 8 HRV-14 1300 4.924 >10 9 HRV-1412550 ND ND 10 HRV-14 2370 ND ND 11 HRV-14 5000 0.646 >10 12 HRV-14 27001.248 >10 13 HRV-14 6570 2.01 >10 14 HRV-14 34600 0.534 >10 15 HRV-14980 27.0 >100 16 HRV-14 7100 1.321 >10 17 HRV-14 2900 2.186 >10 18HRV-14 3140 1.597 >10 19 HRV-14 6650 1.527 >10 20 HRV-14 330 16.42 >10021 HRV-14 1380 ND ND 22 HRV-14 4400 5.719 >10 23 HRV-14 3800 1.546 >1024 HRV-14 5460 3.914 >100 25 HRV-14 690000 0.034 >10 HRV-1A ND 0.089 >10HRV-10 ND 0.148 >10 CAV-21 ND 0.2 >10 ECHO-11 ND 0.044 >10 ENT-70 ND.003 >10 26 HRV-14 188000 0.073 >10 27 HRV-14 11700 1.585 >10 28 HRV-14340000 0.059 >1 HRV-1A ND 0.213 >1 HRV-10 ND 0.066 >1 29 HRV-14 1030000.15 >10 HRV-1A ND 0.054 >10 HRV-10 ND 0.027 >10 HRV-3 ND 0.065 >10HRV-25 ND 0.316 >10 HRV-9 ND 0.119 >10 HRV-39 ND 0.180 >10 30 HRV-142500 3.336 >10 31 HRV-14 900 ND ND 32 HRV-14 8300 ND ND 33 HRV-14 1000000.212 >10 34 HRV-14 520 ND ND 35 HRV-14 125000 0.143 >10 36 HRV-14 593000.17 >10 HRV-1A ND 0.145 >10 HRV-10 ND 0.330 >10 HRV-3 ND 0.145 >10HRV-25 ND 0.329 >10 HRV-9 ND 0.144 >10 HRV-39 ND 0.235 >10 HRV-14 279000.541 >10 37 HRV-14 26400 0.266 >10 38 HRV-1A ND 0.537 >10 HRV-10 ND0.446 >10 HRV-39 ND 0.593 >10 HRV-87 ND 0.097 >10 HRV-2 ND 0.353 >10HRV-3 ND 0.605 >10 HRV-9 ND 0.885 >10 HRV-16 ND 1.49 >10 HRV-25 ND1.51 >10 HRV-14 33000 0.136 >10 39 HRV-1A ND 0.338 >10 HRV-10 ND0.428 >10 HRV-39 ND 0.518 >10 HRV-87 ND 0.083 >10 HRV-2 ND 0.214 >10HRV-3 ND 0.595 >10 HRV-9 ND 0.665 >10 HRV-16 ND 0.952 >10 HRV-25 ND1.32 >10 HRV-14 20100 0.214 >10 40 HRV-14 3175 1.656 >10 41 HRV-14 107000.50 >10 42 HRV-14 42 ND ND 43 HRV-14 85 ND ND 44 HRV-14 1031 ND ND 45HRV-14 629 ND ND 46

[0516] While the invention has been described in terms of preferredembodiments and specific examples, those skilled in the art willrecognize through routine experimentation that various changes andmodifications can be made without departing from the spirit and scope ofthe invention. Thus, the invention should be understood as not beinglimited by the foregoing detailed description, but as being defined bythe appended claims and their equivalents.

We claim:
 1. An antipicornaviral compound having the formula:

wherein: R¹ is an alkylcarbonylalkyl, cycloalkylcarbonylalkyl,arylcarbonylalkyl, heteroarylcarbonylalkyl, alkylcarbonylaminoalkyl,cycloalkylcarbonylaminoalkyl, heterocycloalkylcarbonylaminoalkyl,arylcarbonylaminoalkyl, heteroarylcarbonylaminoalkyl,alkylaminocarbonylalkyl, cycloalkylaminocarbonylalkyl,heterocycloalkylaminocarbonylalkyl, arylaminocarbonylalkyl,heteroarylaminocarbonylalkyl group, where each alkyl, cycloalkyl,heterocycloalkyl, aryl and heteroaryl moiety thereof may beunsubstituted or substituted with one or more suitable substituents;R^(b) is H or an alkyl group, unsubstituted or substituted with one ormore suitable substituents; R^(d) is H, halo, hydroxyl, or an alkyl,alkoxy or alkylthio group, where the alkyl, alkoxy or alkylthio group isunsubstituted or substituted with one or more suitable substituents;R^(c) is a moiety having the formula:

R^(e) and R^(f) are each independently H or a lower alkyl group; m is 0or 1, provided that when m is 1, R^(a) is not an amino-substitutedalkylcarbonylalkyl or amino-substituted alkylcarbonylaminoalkyl group,and when m is 0, R^(a) is selected from an alkylaminocarbonylalkyl,cycloalkylaminocarbonylalkyl, heterocycloalkylaminocarbonylalkyl,arylaminocarbonylalkyl, heteroarylaminocarbonylalkyl andheteroarylcarbonylaminoalkyl group, provided that R^(a) is notsubstituted indolecarbonylaminoalkyl; p is an integer of from 0 to 5; A₁is CH or N; when p is 1, 2, 3, 4, or 5, A₂ is C(R^(g))(R^(h)), N(R^(i)),S, S(O), S(O)₂, or O, and when p is 0, A₂ is C(R^(g))(R^(h))(R^(i)),N(R^(g))(R^(i)), S(R^(g)), S(O)(R^(g)), S(O)₂(R^(g)), or O(R^(g)), whereeach R^(g), R^(h) and R^(i) is independently H or a lower alkyl group;each A₃ present is independently C(R^(g))(R^(h)), N(R^(i)), S, S(O),S(O)₂, or O, where each R^(g), R^(h) and R^(i) is independently H or alower alkyl group; when p is 1, 2, 3, 4, or 5, A₄ is N(R^(j)),C(R^(g))(R^(h)), or O, and when p is 0, A₄ is N(R^(j))(R^(k)),C(R^(g))(R^(h))(R^(i)), and O(R^(k)), where each R^(g), R^(h) and R^(i)is independently H or a lower alkyl group, each R^(j) is H, an alkyl,aryl, or acyl group, and each R^(k) is H or an alkyl or aryl group;provided that no more than two heteroatoms occur consecutively in theabove-depicted ring formed by A₁, (A₂)_(m), (A₃)_(p), A₄, and C═O, whereeach dotted line in the ring depicts a single bond when A₂ is presentand a hydrogen atom when A₂ is absent; and Z and Z¹ are eachindependently H, F, an alkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl group, where the alkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl group is unsubstituted or substituted with one or moresuitable substituents, —C(O)R^(l), —CO₂R^(l), —CN, —C(O)NR^(l)R^(m),—C(O)NR^(l)OR^(m), —C(S)R^(l), —C(S)OR^(l) —C(S)NR^(l)R^(m),—C(═NR^(l))R^(m), —C(═NR^(l))OR^(m), —NO₂, —SOR^(m), —SO₂R^(l),—SO₂NR^(l)R^(m), —SO₂(NR^(l))(OR^(m)), —SONR^(l), —SO₃R^(l),—PO(OR^(l))₂, —PO(OR^(l))(OR^(m)), —PO(NR^(l)R^(m))(OR^(n)),—PO(NR^(l)R^(m))(NR^(n)R^(o)), —C(O)NR^(l)NR^(m)R^(n),—C(S)NR^(l)NR^(m)R^(n), where R^(l), R^(m), R^(n) and R^(o) are eachindependently H or an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl orthioacyl group, where the alkyl, cycloalkyl, aryl, heterocycloalkyl,acyl or thioacyl group is unsubstituted or substituted with one or moresuitable substituents, or where any two of the R^(l), R^(m), R^(n) andR^(o), taken together with the atoms to which they are bonded, form aheterocycloalkyl group, which may be optionally substituted, or Z andR^(d), together with the atoms to which they are bonded, form acycloalkyl or heterocycloalkyl group, where Z and R^(d) are as definedabove except for moieties that cannot form the cycloalkyl orheterocycloalkyl group, or Z and Z¹, together with the atoms to whichthey are bonded, form a cycloalkyl or heterocycloalkyl group, where Zand Z¹ are as defined above; or a prodrug, pharmaceutically acceptablesalt, pharmaceutically active metabolite, or pharmaceutically acceptablesolvate of said compound.
 2. The compound according to claim 1, whereinA is CH or N; A₂ is C(R^(g))(R^(h)), N(R^(i)), S, S(O), S(O)₂, or O,where each R^(g), R^(h) and R^(i) is independently H or a lower alkylgroup; each A₃ present is independently C(R^(g))(R^(h)), N(R^(i)), S,S(O), S(O)₂, or O, where each R^(g), R^(h) and R^(i) is independently Hor a lower alkyl group; when p is 1, 2, 3, 4, or 5, A₄ is N(R^(j)),C(R^(g))(R^(h)), or O, and when p is 0, A₄ is N(R^(j))(R^(k)),C(R^(g))(R^(h))(R^(i)), and O(R^(k)), where each R^(g), R^(h) and R^(i)is independently H or a lower alkyl group, each R^(j) is H, an alkyl,aryl, or acyl group, and each R^(k) is H or an alkyl or aryl group;provided that no more than two heteroatoms occur consecutively in theabove-depicted ring formed by A₁, (A₂)_(m), (A₃)_(p), A₄, and C═O, whereeach dotted line in the ring depicts a single bond when A₂ is presentand a hydrogen atom when A₂ is absent; and Z and Z¹ are eachindependently H, F, an alkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl group, where the alkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl group is unsubstituted or substituted with one or moresuitable substituents, —C(O)R^(l), —CO₂R^(l), —CN, —C(O)NR^(l)R^(m),—C(O)NR^(l)OR^(m), —C(S)R^(l), —C(S)NR^(l)R^(m), —NO₂, —SOR^(m),—SO₂R^(l), —SO₂NR^(l)R^(m), —SO₂(NR^(l))(OR^(m)), —SONR^(l), —SO₃R^(l),—PO(OR^(l))₂, —PO(OR^(l))(OR^(m)), —PO(NR^(l)R^(m))(OR^(n)),—PO(NR^(l)R^(m))(NR^(n)R^(o)), —C(O)NR^(l)NR^(m)R^(n),—C(S)NR^(l)NR^(m)R^(n), where R^(l), R^(m), R^(n) and R^(o) are eachindependently H, an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl orthioacyl group, where the alkyl, cycloalkyl, aryl, heterocycloalkyl,acyl or thioacyl group is unsubstituted or substituted with one or moresuitable substituents, or where any two of the R^(l), R^(m), R^(n) andR^(o), taken together with the atoms to which they are bonded, form aheterocycloalkyl group, which is unsubstituted or substituted with oneor more suitable substituents, or Z and Z¹, together with the atoms towhich they are bonded, form a cycloalkyl or heterocycloalkyl group,where Z and Z¹ are as defined above.
 3. The compound according to claim1 or 2, having the formula:

wherein R^(a′) is an alkyl, cycloalkyl, aryl or heteroaryl group, wheresaid alkyl, cycloalkyl, aryl or heteroaryl group is unsubstituted orsubstituted with one or more suitable substituents, n is 1, 2 or 3, m is1, R^(x) and R^(y) are each independently selected from H and an alkylgroup, unsubstituted or substituted with one or more suitablesubstituents, and R^(b), R^(c), R^(d), Z and Z¹ are as defined in claim1 or 2, respectively, provided that R^(a′) is not an amino-substitutedalkyl group.
 4. The compound according to claim 1 or 2, having theformula:

wherein R^(a′) is an alkyl, cycloalkyl, aryl or heteroaryl group, wheresaid alkyl, cycloalkyl, aryl or heteroaryl group is unsubstituted orsubstituted with one or more suitable substituents, n is 1, 2 or 3, m is1, R^(x) and R^(y) are each independently selected from H and an alkylgroup, unsubstituted or substituted with one or more suitablesubstituents, and R^(b), R^(c), R^(d), Z and Z¹ are as defined in claim1 or 2, respectively, provided that R^(a′) is not an amino-substitutedalkyl group.
 5. The compound according to claim 1 or 2, having theformula:

wherein R^(a′) is an alkyl, aryl, cycloalkyl, heterocycloalkyl orheteroaryl group, where said alkyl, aryl, cycloalkyl, heterocycloalkyland heteroaryl group is unsubstituted or substituted with one or moresuitable substituents, n is 1, 2 or 3, R^(x) and R^(y) are eachindependently selected from H and an alkyl group, unsubstituted orsubstituted with one or more suitable substituents, and R^(b), R^(c),R^(d), Z and Z¹ are as defined as in claim 1 or 2, respectively.
 6. Thecompound according to claim 1 or 2, wherein said substituted alkyl,aryl, cycloalkyl, heterocycloalkyl or heteroaryl comprises one or moresubstituents independently selected from an alkyl, aryl, cycloalkyl,heterocycloalkyl, heteroaryl, nitro, amino, cyano, halo, hydroxyl,alkoxy, alkylenedioxy, aryloxy, cycloalkoxy, heterocycloalkoxy,heteroaryloxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy,arylcarbonyl, arylcarbonyloxy, aryloxycarbonyl, cycloalkylcarbonyl,cycloalkylcarbonyloxy, cycloalkyoxycarbonyl, heteroarylcarbonyl,heteroarylcarbonyloxy, heteroaryloxycarbonyl, heterocycloalkylcarbonyl,heterocycloalkylcarbonyloxy, heterocycloalkyoxycarbonyl, carboxyl,carbamoyl, formyl, keto, thioketo, sulfo, alkylamino, cycloalkylamino,arylamino, heterocycloalkylamino, heteroarylamino, dialkylamino,alkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl,heterocycloalkylaminocarbonyl, heteroarylaminocarbonyl,dialkylaminocarbonyl, alkylaminothiocarbonyl,cycloalkylaminothiocarbonyl, arylaminothiocarbonyl,heterocycloalkylaminothiocarbonyl, heteroarylaminothiocarbonyl,dialkylaminothiocarbonyl, alkylsulfonyl, arylsulfonyl, alkylsulfenyl,arylsulfenyl, alkylcarbonylamino, cycloalkylcarbonylamino,arylcarbonylamino, heterocycloalkylcarbonylamino,heteroarylcarbonylamino, alkylthiocarbonylamino,cycloalkylthiocarbonylamino, arylthiocarbonylamino,heterocycloalkylthiocarbonylamino, heteroarylthiocarbonylamino,alkylsulfonyloxy, arylsulfonyloxy, alkylsulfonylamino,arylsulfonylamino, mercapto, alkylthio, arylthio and heteroarylthiogroup, where any of the alkyl, alkylene, aryl, cycloalkyl,heterocycloalkyl, heteroaryl moieties present in the above substituentsmay be further substituted with one or more suitable substituents. 7.The compound according to claim 6, wherein said substituted alkyl,alkylene, aryl, cycloalkyl, heterocycloalkyl, heteroaryl moieties may befurther substituted with one or more substituents selected from nitro,amino, cyano, halo, haloalkyl, haloaryl, hydroxyl, keto, hydroxamino,alkylamino, dialkylamino, mercapto, and unsubstituted alkyl, aryl,cycloalkyl, heterocycloalkyl, heteroaryl, alkoxy, aryloxy, alkylthio orarylthio groups and wherein any of the aryl or heteroaryl moieties maybe substituted with alkylenedioxy.
 8. An antipicornaviral compoundhaving the formula:

wherein: W is CH or N; R^(a′) is an alkyl, cycloalkyl, aryl orheteroaryl group, where said alkyl, cycloalkyl, aryl, and heteroarylgroup is unsubstituted or substituted with one or more suitablesubstituents, provided that R^(a′) is not an amino-substituted alkylgroup; R⁴ and R⁶ are each independently H or a lower alkyl group; R⁵ isH or an alkyl group; R⁷ is a moiety having the formula:

wherein: R⁸ and R⁹ are each independently H or lower alkyl; p is aninteger of from 1 to 5; A is CH or N; when p is 1, 2, 3, 4, or 5, A₂ isC(R¹⁰)(R¹¹), N(R¹²), S, S(O), S(O)₂, or O, and when p is 0, A₂ isC(R¹⁰)(R¹¹)(R¹²), N(R¹⁰)(R¹²), S(R¹⁰), S(O)(R¹⁰), S(O)₂(R¹⁰), or O(R¹⁰)where each R¹⁰, R¹¹ and R¹² is independently H or a lower alkyl group;each A₃ present is independently C(R¹⁰)(R¹¹), N(R¹²), S, S(O), S(O)₂, orO, where each R¹⁰, R¹¹ and R¹² is independently H or a lower alkylgroup; when p is 1, 2, 3, 4, or 5, A₄ is N(R¹³), C(R¹⁰)(R¹¹), or O, andwhen p is 0, A₄ is N(R¹³)(R¹⁴), C(R¹⁰)(R¹¹)(R¹²), and O(R¹⁴), where eachR¹⁰, R¹¹ and R¹² is independently H or a lower alkyl group, each R¹³ isH or an alkyl, aryl, or acyl group, and each R¹⁴ is H or an alkyl oraryl group; provided that no more than two heteroatoms occurconsecutively in the above-depicted ring formed by A₁, (A₂)_(m),(A₃)_(p), A₄, and C═O, where each dotted line in the ring depicts asingle bond when A₂ is present and a hydrogen atom when A₂ is absent;and Z and Z¹ are each independently H, F, an alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl group, where the alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl group is unsubstituted orsubstituted with one or more suitable substituents, —C(O)R¹⁵, —CO₂R¹⁵,—CN, —C(O)NR¹⁵R¹⁶, —C(O)NR¹⁵OR¹⁶,—C(S)R¹⁵, —C(S)OR¹⁵, —C(S)NR¹⁵R¹⁶,—C(═NR¹⁵)R¹⁶, —C(═NR¹⁵)OR¹⁶, —NO₂, —SOR¹⁶, —SO₂R¹⁵, —SO₂NR¹⁵R¹⁶,—SO₂(NR¹⁵)(OR¹⁶), —SONR¹⁵, —SO₃R¹⁵, —PO(OR¹⁵)₂, —PO(OR¹⁵)(OR¹⁶),—PO(NR¹⁵R¹⁶)(OR¹⁷), —PO(NR¹⁵R¹⁶)(NR¹⁷R¹⁸), —C(O)NR¹⁵NR¹⁶R¹⁷,—C(S)NR¹⁵NR¹⁶R¹⁷, where R¹⁵, R¹⁶, R¹⁷ and R¹⁸ are each independently Hor an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacyl group,where the alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacylgroup is unsubstituted or substituted with one or more suitablesubstituents, or where any two of the R¹⁵, R¹⁶, R¹⁷ and R¹⁸, takentogether with the atoms to which they are bonded, form aheterocycloalkyl group, which is unsubstituted or substituted with oneor more suitable substituents, or Z and Z¹, together with the atoms towhich they are bonded, form a cycloalkyl or heterocycloalkyl group,where Z and Z¹ are as defined above; or a prodrug, pharmaceuticallyacceptable salt, pharmaceutically active metabolite, or pharmaceuticallyacceptable solvate of said compound.
 9. The compound according to claim8, wherein: A is CH or N; A₂ is C(R¹⁰)(R¹¹), N(R¹²), S, S(O), S(O)₂, orO, where each R¹⁰, R¹¹ and R¹² is independently H or a lower alkylgroup; each A₃ present is independently C(R¹⁰)(R¹¹), N(R¹²), S, S(O),S(O)₂, or O, where each R¹⁰, R¹¹ and R¹² is independently H or a loweralkyl group; when p is 1, 2, 3, 4, or 5, A₄ is N(R¹³), C(R¹⁰)(R¹¹), orO, and when p is 0, A₄ is N(R¹³)(R¹⁴), C(R¹⁰)(R¹¹)(R¹²), and O(R¹⁴),where each R¹⁰, R¹¹ and R¹² is independently H or a lower alkyl group,each R¹³ is H or an alkyl, aryl, or acyl group, and each R¹⁴ is H or analkyl or aryl group; provided that no more than two heteroatoms occurconsecutively in the above-depicted ring formed by A₁, (A₂)_(m),(A₃)_(p), A₄, and C═O, where each dotted line in the ring depicts asingle bond when A₂ is present and a hydrogen atom when A₂ is absent;and Z and Z¹ are each independently H, F, an alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl group, where the alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl group is unsubstituted orsubstituted with one or more suitable substituents, —C(O)R¹⁵, —CO₂R¹⁵,—CN, —C(O)NR¹⁵R¹⁶, —C(O)NR¹⁵OR¹⁶,—C(S)R¹⁵, —C(S)NR¹⁵R¹⁶, —NO₂, —SOR¹⁶,—SO₂R¹⁵, —SO₂NR¹⁵R¹⁶, —SO₂(NR¹⁵)(OR¹⁶), SONR¹⁵, —SO₃R¹⁵, —PO(OR¹⁵)₂,—PO(OR¹⁵)(OR¹⁶), —PO(NR¹⁵R¹⁶)(OR¹⁷), —PO(NR¹⁵R¹⁶)(NR¹⁷R¹⁸),—C(O)NR¹⁵NR¹⁶R¹⁷,—C(S)NR¹⁵NR¹⁶R¹⁷, where R¹⁵, R¹⁶, R¹⁷ and R¹⁸ are eachindependently H or an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl orthioacyl group, where the alkyl, cycloalkyl, aryl, heterocycloalkyl,acyl or thioacyl group is unsubstituted or substituted with one or moresuitable substituents, or where any two of the R¹⁵, R¹⁶, R¹⁷ and R¹⁸,taken together with the atoms to which they are bonded, form aheterocycloalkyl group, which is unsubstituted or substituted with oneor more suitable substituents, or Z and Z¹, together with the atoms towhich they are bonded, form a cycloalkyl or heterocycloalkyl group,where Z and Z¹ are as defined above.
 10. The compound according to claim8 or 9, having the formula:

wherein R^(a′) is an alkyl, cycloalkyl, aryl or heteroaryl group, wheresaid alkyl, cycloalkyl, aryl, and heteroaryl group is unsubstituted orsubstituted with one or more suitable substituents, and R⁴, R⁵, R⁶, R⁷,Z and Z¹ are defined as in claim 8 or 9, respectively, provided thatR^(a′) is not amino-substituted alkyl.
 11. The compound according toclaim 8 or 9, having the formula:

wherein R^(a′) is an alkyl, cycloalkyl, aryl or heteroaryl group, wheresaid alkyl, cycloalkyl, aryl, and heteroaryl group is unsubstituted orsubstituted with one or more suitable substituents, and R⁴, R⁵, R⁶, R⁷,Z and Z¹ are defined as in claims 8 or 9, repsectively, provided thatR^(a′) is not amino-substituted alkyl.
 12. An antipicornaviral compoundhaving the formula:

wherein: R¹ is H, halo or an alkoxy, alkyl, aryl, cycloalkyl,heterocycloalkyl or heteroaryl group, where the alkoxy, alkyl,cycloalkyl, heterocycloalkyl or heteroaryl group is unsubstituted orsubstituted with one or more suitable substituents; R² and R³ are eachindependently H, halo or an alkoxy or lower alkyl group, where thealkoxy or lower alkyl group is unsubstituted or substituted with one ormore suitable substituents; or R¹ together with R² form a cycloalkyl,heterocycloalkyl, aryl or heteroaryl ring, where the cycloalkyl,heterocycloalkyl, aryl or heteroaryl ring is unsubstituted orsubstituted with one or more suitable substituents; R⁴ and R⁶ are eachindependently H or a lower alkyl group, unsubstituted or substitutedwith one or more suitable substituents; R⁵ is H or an alkyl group,unsubstituted or substituted with one or more suitable substituents; R⁷is a moiety having the formula:

wherein: R⁸ and R⁹ are each independently H or a lower alkyl group; m is0 or 1; p is an integer of from 0 to 5; A₁ is CH or N; when p is 1, 2,3, 4, or 5, A₂ is C(R¹⁰)(R¹¹), N(R¹²), S, S(O), S(O)₂, or O, and when pis 0, A₂ is C(R¹⁰)(R¹¹)(R¹²), N(R¹⁰)(R¹²), S(R¹⁰), S(O)(R¹⁰),S(O)₂(R¹⁰), or O(R¹⁰) where each R¹⁰, R¹¹ and R¹² is independently H ora lower alkyl group; each A₃ present is independently C(R¹⁰)(R¹¹),N(R¹²), S, S(O), S(O)₂, or O, where each R¹⁰, R¹¹ and R¹² isindependently H or a lower alkyl group; when p is 1, 2, 3, 4, or 5, A₄is N(R¹³), C(R¹⁰)(R¹¹), or O, and when p is 0, A₄ is N(R¹³)(R¹⁴),C(R¹⁰)(R¹¹)(R¹²), and O(R¹⁴), where each R¹⁰, R¹¹ and R¹² is eachindependently H or a lower alkyl group, each R¹³ is H or an alkyl, aryl,or acyl group, and each R¹⁴ is H or an alkyl or aryl group; providedthat no more than two heteroatoms occur consecutively in theabove-depicted ring formed by A₁, (A₂)_(m), (A₃)_(p), A₄, and C═O, whereeach dotted line in the ring depicts a single bond when A₂ is presentand a hydrogen atom when A₂ is absent; and Z and Z¹ are eachindependently H, F, an alkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl group, where the alkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl group is unsubstituted or substituted with one or moresuitable substituents, —C(O)R¹⁵, —CO₂R¹⁵, —CN, —C(O)NR¹⁵R¹⁶,—C(O)NR¹⁵OR¹⁶, —C(S)R¹⁵, —C(S)OR¹⁵, —C(S)NR¹⁵R¹⁶, —C(═NR¹⁵)R¹⁶,—C(═NR¹⁵)OR¹⁶, —NO₂, —SOR¹⁶, —SO₂R¹⁵, —SO₂NR¹⁵R¹⁶, —SO₂(NR¹⁵)(OR¹⁶),SONR¹⁵, —SO₃R¹⁵, —PO(OR¹⁵)₂, —PO(OR¹⁵)(OR(¹⁶), —PO(NR¹⁵R¹⁶)(OR¹⁷),—PO(NR¹⁵R¹⁶)(NR¹⁷R¹⁸), —C(O)NR¹⁵NR¹⁶R¹⁷, —C(S)NR¹⁵NR¹⁶R¹⁷, where R¹⁵,R¹⁶, R¹⁷ and R¹⁸ are each independently H or an alkyl, cycloalkyl, aryl,heterocycloalkyl, acyl or thioacyl group, where the alkyl, cycloalkyl,aryl, heterocycloalkyl, acyl or thioacyl group is unsubstituted orsubstituted with one or more suitable substituents, or where any two ofthe R¹⁵, R¹⁶, R¹⁷ and R^(18,) taken together with the atoms to whichthey are bonded, form a heterocycloalkyl group, which is unsubstitutedor substituted with one or more suitable substituents, or Z and Z¹,together with the atoms to which they are bonded, form a cycloalkyl orheterocycloalkyl group, where Z and Z¹ are as defined above; or aprodrug, pharmaceutically acceptable salt, pharmaceutically activemetabolite, or pharmaceutically acceptable solvate thereof of saidcompound.
 13. An antipicornaviral compound having the formula:

wherein: R¹ is H, halo or an alkoxy, alkyl, aryl, cycloalkyl,heterocycloalkyl, or heteroaryl group, where the alkoxy, alkyl,cycloalkyl, heterocycloalkyl or heteroaryl group is unsubstituted orsubstituted with one or more suitable substituents; R² and R³ are eachindependently H, halo or an alkoxy or lower alkyl group, where thealkoxy or lower alkyl group is unsubstituted or substituted with one ormore suitable substituents; or R¹ together with R² form a cycloalkyl,heterocycloalkyl, aryl or heteroaryl ring, where the cycloalkyl,heterocycloalkyl, aryl or heteroaryl ring is unsubstituted orsubstituted with one or more suitable substituents; R⁴ and R⁶ are eachindependently H or a lower alkyl group, unsubstituted or substitutedwith one or more suitable substituents; R⁵ is H or an alkyl group,unsubstituted or substituted with one or more suitable substituents; R⁷is a moiety having the formula:

wherein: R⁸ and R⁹ are each independently H or a lower alkyl group; m is0 or 1, provided that when m is 0 and R¹ together with R² form an arylring, the aryl ring is unsubstituted; p is an integer of from 0 to 5; A₁is CH or N; when p is 1, 2, 3, 4, or 5, A₂ is C(R¹⁰)(R¹¹), N(R¹²), S,S(O), S(O)₂, or O, and when p is 0, A₂ is C(R¹⁰)(R¹¹)(R¹²), N(R¹⁰)(R¹²),S(R¹⁰), S(O)(R¹⁰), S(O)₂(R¹⁰), or O(R¹⁰) where each R¹⁰, R¹¹ and R¹² isindependently H or a lower alkyl group; each A₃ present is independentlyC(R¹⁰)(R¹¹), N(R¹²), S, S(O), S(O)₂, or O, where each R¹⁰, R¹¹ and R¹²is independently H or a lower alkyl group; when p is 1, 2, 3, 4, or 5,A₄ is N(R¹³), C(R¹⁰)(R¹¹), or O, and when p is 0, A₄ is N(R¹³)(R¹⁴),C(R¹⁰)(R¹¹)(R¹²), and O(R¹⁴), where each R¹⁰, R¹¹ and R¹² isindependently H or a lower alkyl group, each R¹³ is H or an alkyl, aryl,or acyl group, and each R¹⁴ is H or an alkyl or aryl group; providedthat no more than two heteroatoms occur consecutively in theabove-depicted ring formed by A₁, (A₂)_(m), (A₃)_(p), A₄, and C═O, whereeach dotted line in the ring depicts a single bond when A₂ is presentand a hydrogen atom when A₂ is absent; and Z and Z¹ are eachindependently H, F, an alkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl group, where the alkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl group is unsubstituted or substituted with one or moresuitable substituents, —C(O)R¹⁵, —CO₂R¹⁵, —CN, —C(O)NR¹⁵R¹⁶,—C(O)NR¹⁵OR¹⁶, —C(S)R¹⁵, —C(S)OR¹⁵, —C(S)NR¹⁵R¹⁶, —C(═NR¹⁵)R¹⁶,—C(═NR¹⁵)OR¹⁶, —NO₂, —SOR¹⁶, —SO₂R¹⁵, —SO₂NR¹⁵R¹⁶, —SO₂(NR¹⁵)(OR¹⁶),—SONR¹⁵, —SO₃R¹⁵, —PO(OR¹⁵)₂, —PO(OR¹⁵)(OR¹⁶), —PO(NR¹⁵R¹⁶)(OR¹⁷),—PO(NR¹⁵R¹⁶)(NR¹⁷R¹⁸), —C(O)NR¹⁵NR¹⁶R¹⁷, —C(S)NR¹⁵NR¹⁶R¹⁷, where R¹⁵,R¹⁶, R¹⁷ and R¹⁸ are each independently H or an alkyl, cycloalkyl, aryl,heterocycloalkyl, acyl or thioacyl group, where the alkyl, cycloalkyl,aryl, heterocycloalkyl, acyl or thioacyl group is unsubstituted orsubstituted with one or more suitable substituents, or where any two ofthe R¹⁵, R¹⁶, R¹⁷ and R¹⁸, taken together with the atoms to which theyare bonded, form a heterocycloalkyl group, which is unsubstituted orsubstituted with one or more suitable substituents, or Z and Z¹,together with the atoms to which they are bonded, form a cycloalkyl orheterocycloalkyl group, where Z and Z¹ are as defined above; or aprodrug, pharmaceutically acceptable salt, pharmaceutically activemetabolite, or pharmaceutically acceptable solvate of said compound. 14.The compound according to claim 13, having the formula:

wherein: each R^(z) is H or a suitable substituent and n_(z) is aninteger from 1 to 4; R⁷ is a moiety having the formula:

wherein: R⁸and R⁹ are each independently H or a lower alkyl group; p isan integer of from 1 to 5; A₁ is CH or N; when p is 1, 2, 3, 4, or 5, A₂is C(R¹⁰)(R¹¹), N(R¹²), S, S(O), S(O)₂, or O, and when p is 0, A₂ isC(R¹⁰)(R¹¹)(R¹²), N(R¹⁰)(R¹²), S(R¹⁰), S(O)(R¹⁰), S(O)₂(R¹⁰), or O(R¹⁰)where each R¹⁰, R¹¹ and R¹² is independently H or a lower alkyl group;each A₃ present is independently C(R¹⁰)(R¹¹), N(R¹²), S, S(O), S(O)₂, orO, where each R¹⁰, R¹¹ and R¹² is independently H or a lower alkylgroup; A₄ is N(R¹³), C(R¹⁰)(R¹¹), or O, where R¹⁰ and R¹¹ are eachindependently H or a lower alkyl group, and R¹³ is H or an alkyl, arylor acyl group; provided that no more than two heteroatoms occurconsecutively in the above-depicted ring formed by A₁, (A₂)_(m),(A₃)_(p), A₄, and C═O; and R³, R⁴, R⁵, R⁶, Z and Z¹ are defined as inclaim
 13. 15. The compound according to claim 14, wherein each R^(z) isindependently selected from H, halo, alkoxy, unsubstituted lower alkyl,haloalkyl, and lower alkoxyalkyl.
 16. The compound according to any oneof claims 12, 13 or 14, wherein: A₁ is CH or N; A₂ is C(R¹⁰)(R¹¹),N(R¹²), S, S(O), S(O)₂, or O, where each R¹⁰, R¹¹ and R¹² isindependently H or a lower alkyl group; each A₃ present is independentlyC(R¹⁰)(R¹¹), N(R¹²), S, S(O), S(O)₂, or O, where each R¹⁰, R¹¹ and R¹²is independently H or a lower alkyl group; when p is 1, 2, 3, 4, or 5,A₄ is N(R¹³), C(R¹⁰)(R¹¹), or O, and when p is 0, A₄ is N(R¹³)(R¹⁴),C(R¹⁰)(R¹¹)(R¹²), and O(R¹⁴), where each R¹⁰, R¹¹ and R¹² isindependently H or a lower alkyl group, each R¹³ is H or an alkyl, aryl,or acyl group, and each R¹⁴ is H or an alkyl or aryl group; providedthat no more than two heteroatoms occur consecutively in theabove-depicted ring formed by A₁, (A₂)_(m), (A₃)_(p), A₄, and C═O, whereeach dotted line in the ring depicts a single bond when A₂ is presentand a hydrogen atom when A₂ is absent; and Z and Z¹ are eachindependently H, F, an alkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl group, where the alkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl group is unsubstituted or substituted with one or moresuitable substituents, —C(O)R¹⁵, —CO₂R¹⁵, —CN, —C(O)NR¹⁵R¹⁶,—C(O)NR¹⁵OR¹⁶, —C(S)R¹⁵, —C(S)NR¹⁵R¹⁶, —NO₂, —SOR¹⁶, —SO₂R¹⁵,—SO₂NR¹⁵R¹⁶, —SO₂(NR¹⁵)(OR¹⁶), —SONR¹⁵, —SO₃R¹⁵, —PO(OR¹⁵)₂,—PO(OR¹⁵)(OR¹⁶), —PO(NR¹⁵R¹⁶)(OR¹⁷), —PO(NR¹⁵R¹⁶)(NR¹⁷R¹⁸),—C(O)NR¹⁵NR¹⁶R¹⁷, —C(S)NR¹⁵NR¹⁶R¹⁷, where R¹⁵, R¹⁶, R¹⁷ and R¹⁸ are eachindependently H or an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl orthioacyl group, where the alkyl, cycloalkyl, aryl, heterocycloalkyl,acyl or thioacyl group is unsubstituted or substituted with one or moresuitable substituents, or where any two of the R¹⁵, R¹⁶, R¹⁷ and R¹⁸,taken together with the atoms to which they are bonded, form aheterocycloalkyl group, which is unsubstituted or substituted with oneor more suitable substituents, or Z and Z¹, together with the atoms towhich they are bonded, form a cycloalkyl or heterocycloalkyl group,where Z and Z¹ are as defined above.
 17. The compound according to anyone of claims 12, 13 or 14, wherein said substituted alkyl, aryl,cycloalkyl, heterocycloalkyl or heteroaryl comprises one or moresubstituents independently selected from an alkyl, aryl, cycloalkyl,heterocycloalkyl, heteroaryl, nitro, amino, cyano, halo, hydroxyl,alkoxy, alkylenedioxy, aryloxy, cycloalkoxy, heterocycloalkoxy,heteroaryloxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy,arylcarbonyl, arylcarbonyloxy, aryloxycarbonyl, cycloalkylcarbonyl,cycloalkylcarbonyloxy, cycloalkyoxycarbonyl, heteroarylcarbonyl,heteroarylcarbonyloxy, heteroaryloxycarbonyl, heterocycloalkylcarbonyl,heterocycloalkylcarbonyloxy, heterocycloalkyoxycarbonyl, carboxyl,carbamoyl, formyl, keto, thioketo, sulfo, alkylamino, cycloalkylamino,arylamino, heterocycloalkylamino, heteroarylamino, dialkylamino,alkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl,heterocycloalkylaminocarbonyl, heteroarylaminocarbonyl,dialkylaminocarbonyl, alkylaminothiocarbonyl,cycloalkylaminothiocarbonyl, arylaminothiocarbonyl,heterocycloalkylaminothiocarbonyl, heteroarylaminothiocarbonyl,dialkylaminothiocarbonyl, alkylsulfonyl, arylsulfonyl, alkylsulfenyl,arylsulfenyl, alkylcarbonylamino, cycloalkylcarbonylamino,arylcarbonylamino, heterocycloalkylcarbonylamino,heteroarylcarbonylamino, alkylthiocarbonylamino,cycloalkylthiocarbonylamino, arylthiocarbonylamino,heterocycloalkylthiocarbonylamino, heteroarylthiocarbonylamino,alkylsulfonyloxy, arylsulfonyloxy, alkylsulfonylamino,arylsulfonylamino, mercapto, alkylthio, arylthio and heteroarylthiogroup, where any of the alkyl, alkylene, aryl, cycloalkyl,heterocycloalkyl, heteroaryl moieties present in the above substituentsmay be further substituted with one or more suitable substituents. 18.The compound according to any one of claims 12, 13 or 14, wherein saidsubstituted alkyl, alkylene, aryl, cycloalkyl, heterocycloalkyl,heteroaryl moieties may be further substituted with one or more suitablesubstituents selected from nitro, amino, cyano, halo, haloalkyl,haloaryl, hydroxyl, keto, hydroxamino, alkylamino, dialkylamino,mercapto, and unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl,heteroaryl, alkoxy, aryloxy, alkylthio or arylthio groups and whereinsaid aryl or heteroaryl moieties may be substituted with alkylenedioxy.19. An antipicornaviral compound having the formula:

wherein: R^(a′) is an alkyl, aryl, cycloalkyl, heterocycloalkyl orheteroaryl, unsubstituted or substituted with one or more suitablesubstituents,; R⁵ is H or an alkyl group, unsubstituted or substitutedwith one or more suitable substituents,; each R⁶ is independently H or alower alkyl group, unsubstituted or substituted with one or moresuitable substituents,; R⁷ is a moiety having the formula:

wherein: R⁸ and R⁹ are each independently H or a lower alkyl group; m is0 or 1; p is an integer of from 0 to 5; A₁ is CH or N; when p is 1, 2,3, 4, or 5, A₂ is C(R¹⁰)(R¹¹), N(R¹²), S, S(O), S(O)₂, or O, and when pis 0, A₂ is C(R¹⁰)(R¹¹)(R¹²), N(R¹⁰)(R¹²), S(R¹⁰), S(O)(R¹⁰),S(O)₂(R¹⁰), or O(R¹⁰), where each R¹⁰, R¹¹ and R¹² is independently H ora lower alkyl group; each A₃ present is independently C(R¹⁰)(R¹¹),N(R¹²), S, S(O), S(O)₂, or O, where each R¹⁰, R¹¹ and R¹² is eachindependently H or a lower alkyl group; when p is 1, 2, 3, 4, or 5, A₄is N(R¹³), C(R¹⁰)(R¹¹), or O, and when p is 0, A₄ is N(R¹³)(R¹⁴),C(R¹⁰)(R¹¹)(R¹²), and O(R¹⁴), where each R¹⁰, R¹¹ and R¹² isindependently H or a lower alkyl group, each R¹³ is H or an alkyl, aryl,or acyl group, and each R¹⁴ is H or an alkyl or aryl group; providedthat no more than two heteroatoms occur consecutively in theabove-depicted ring formed by A₁, (A₂)_(m), (A₃)_(p), A₄, and C═O, whereeach dotted line in the ring depicts a single bond when A₂ is presentand a hydrogen atom when A₂ is absent; and Z and Z¹ are eachindependently H, F, an alkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl group, where the alkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl group is unsubstituted or substituted with one or moresuitable substituents, —C(O)R¹⁵, —CO₂R¹⁵, —CN, —C(O)NR¹⁵R¹⁶,—C(O)NR¹⁵OR¹⁶, —C(S)R¹⁵, —C(S)OR¹⁵, —C(S)NR¹⁵R¹⁶, —C(═NR¹⁵)R¹⁶,—C(═NR¹⁵)OR¹⁶, —NO₂, —SOR¹⁶, —SO₂R¹⁵, —SO₂NR¹⁵R¹⁶, —SO₂(NR¹⁵)(OR¹⁶),—SONR¹⁵, —SO₃R¹⁵, —PO(OR¹⁵)₂,—PO(OR¹⁵)(OR¹⁶), —PO(NR¹⁵R¹⁶)(OR¹⁷),—PO(NR¹⁵R¹⁶)(NR¹⁷R¹⁸), —C(O)NR¹⁵NR¹⁶R¹⁷, —C(S)NR¹⁵NR¹⁶R¹⁷, where R¹⁵,R¹⁶, R¹⁷ and R¹⁸ are each independently H or an alkyl, cycloalkyl, aryl,heterocycloalkyl, acyl or thioacyl group, where the alkyl, cycloalkyl,aryl, heterocycloalkyl, acyl or thioacyl group is unsubstituted orsubstituted with one or more suitable substituents, or where any two ofthe R¹⁵, R¹⁶, R¹⁷ and R¹⁸, taken together with the atoms to which theyare bonded, form a heterocycloalkyl group, which is unsubstituted orsubstituted with one or more suitable substituents, or Z and Z¹,together with the atoms to which they are bonded, form a cycloalkyl orheterocycloalkyl group, where Z and Z¹ are as defined above; or aprodrug, pharmaceutically acceptable salt, pharmaceutically activemetabolite, or pharmaceutically acceptable solvate of said compound. 20.The compound according to claim 19, wherein: A₁ is CH or N; A₂ isC(R¹⁰)(R¹¹), N(R¹²), S, S(O), S(O)₂, or O, where each R¹⁰, R¹¹ and R¹²is independently H or a lower alkyl group; each A₃ present isindependently C(R¹⁰)(R¹¹), N(R¹²), S, S(O), S(O)₂, or O, where each R¹⁰,R¹¹ and R¹² is independently H or a lower alkyl group; when p is 1, 2,3, 4, or 5, A₄ is N(R¹³), C(R¹⁰)(R¹¹), or O, and when p is 0, A₄ isN(R¹³)(R¹⁴), C(R¹⁰)(R¹¹)(R¹²), and O(R¹⁴), where each R¹⁰, R¹¹ and R¹²is independently H or a lower alkyl group, each R¹³ is H or an alkyl,aryl, or acyl group, and each R¹⁴ is H or an alkyl or aryl group;provided that no more than two heteroatoms occur consecutively in theabove-depicted ring formed by A₁, (A₂)_(m), (A₃)_(p), A₄, and C═O, whereeach dotted line in the ring depicts a single bond when A₂ is presentand a hydrogen atom when A₂ is absent; and Z and Z¹ are eachindependently H, F, an alkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl group, where the alkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl group is unsubstituted or substituted with one or moresuitable substituents, —C(O)R¹⁵, —CO₂R¹⁵, —CN, —C(O)NR¹⁵R¹⁶,—C(O)NR¹⁵OR¹⁶, —C(S)R¹⁵, —C(S)NR¹⁵R¹⁶, —NO₂, —SOR¹⁶, —SO₂R¹⁵,—SO₂NR¹⁵R¹⁶, —SO₂(NR¹⁵)(OR¹⁶), —SONR¹⁵, —SO₃R¹⁵, —PO(OR¹⁵)₂,—PO(OR¹⁵)(OR¹⁶), —PO(NR¹⁵R¹⁶)(OR¹⁷), —PO(NR¹⁵R¹⁶)(NR¹⁷R¹⁸),—C(O)NR¹⁵NR¹⁶R¹⁷, —C(S)NR¹⁵NR¹⁶R¹⁷, where R¹⁵, R¹⁶, R¹⁷ and R¹⁸ are eachindependently H or an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl orthioacyl group, where the alkyl, cycloalkyl, aryl, heterocycloalkyl,acyl or thioacyl group is unsubstituted or substituted with one or moresuitable substituents, or where any two of the R¹⁵, R¹⁶, R¹⁷ and R¹⁸,taken together with the atoms to which they are bonded, form aheterocycloalkyl group, which is unsubstituted or substituted with oneor more suitable substituents, or Z and Z¹, together with the atoms towhich they are bonded, form a cycloalkyl or heterocycloalkyl group,where Z and Z¹ are as defined above.
 21. The compound according to anyone of claims 8, 9, 12, 13, 14, 19 or 20, wherein R⁵ is H or a loweralkyl, arylalkyl, heteroarylalkyl or cycloalkylalkyl group, astraight-chain saturated hydrocarbon moiety or an unsaturatedhydrocarbon moiety, where said lower alkyl, arylalkyl, heteroarylalkylor cycloalkylalkyl group is unsubstituted or substituted with one ormore suitable substituents.
 22. The compound according to claim 21,wherein R⁵ is H or a methyl, ethyl, n-propyl, iso-propyl, n-butyl,sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl,3-methyl-3-buten-1-yl, -methylcyclohexyl, -methylthienyl or benzylgroup, unsubstituted or substituted with one or more suitablesubstituents.
 23. The compound according to claim 16, wherein R⁵ is H ora methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl,-methylcyclohexyl, -methylthienyl or benzyl group, unsubstituted orsubstituted with one or more suitable substituents.
 24. The compoundaccording to claim 21, wherein said substituted methyl, ethyl, n-propyl,iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl,2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl group issubstituted by one or more substituents independently selected fromhalo, alkoxy, aryloxy, alkylthio and arylthio.
 25. The compoundaccording to claim 21, wherein the thienyl moiety of the -methylthienylgroup is substituted by one or more substituents independently selectedfrom lower alkyl, lower alkoxy, hydroxy, amino, alkylamino, dialkylaminoand halo.
 26. The compound according to claim 21, wherein the phenylmoiety of the substituted benzyl is substituted by one or moresubstituents independently selected from lower alkyl, lower alkoxy,alkylenedioxy, hydroxy, amino, alkylamino, dialkylamino and halo. 27.The compound according to any one of claims 8, 9, 12, 13, 14, 19 or 20,wherein R⁵ is H, ethyl, 2-propyn-1-yl, methylcyclohexyl, or substitutedor unsubstituted benzyl, where the phenyl moiety of the substitutedbenzyl comprises one or more substituents independently selected fromlower alkyl, lower alkoxy and halo.
 28. The compound according to claim16, wherein R⁵ is H, ethyl, 2-propyn-1-yl, methylcyclohexyl, orsubstituted or unsubstituted benzyl, where the phenyl moiety of thesubstituted benzyl comprises one or more substituents independentlyselected from lower alkyl, lower alkoxy and halo.
 29. The compound,prodrug, pharmaceutically acceptable salt, pharmaceuticaly activemetabolite, or pharmaceutically acceptable salt according to any one ofclaims 8, 9, 12, 13, 14, 19 or 20, where m is 0 and p is 0 or m is 1 andp is 1 or
 2. 30. The compound according to any one of claims 8, 9, 12,13, 14, 19 or 20, wherein R⁷ is selected from —CH₂CH₂C(O)NH₂;—CH₂CH₂C(O)NH-alkyl; —CH₂NHC(O)CH₃; and

where n is 1 or
 2. 31. The compound according to claim 16, wherein R⁷ isselected from —CH₂CH₂C(O)NH₂; —CH₂CH₂C(O)NH-alkyl; —CH₂NHC(O)CH₃; and

where n is 1 or
 2. 32. The compound according to any one of claims 8, 9,12, 13, 14, 19 or 20, wherein R⁷ is


33. The compound, prodrug, pharmaceutically acceptable salt,pharmaceutically active metabolite, or pharmaceutically acceptablesolvate according to any one of claims 8, 12, 13 or 19, wherein Z and Z¹are each independently selected from H, alkyl, where the alkyl isunsubstituted or substituted with one or more suitable substituents, and—CO₂R¹⁵ or taken together with the atom to which they are attached, forma heterocycloalkyl group, which is optionally substituted with one ormore suitable substituents.
 34. The compound, prodrug, pharmaceuticallyacceptable salt, pharmaceutically active metabolite, or pharmaceuticallyacceptable solvate according to claim 9, wherein Z and Z¹ are eachindependently selected from H, lower alkyl which is unsubstituted orsubstituted with one or more suitable substituents, —CO₂H, —CO₂-alkyland —CO₂-cycloalkyl, or taken together with the atom to which they areattached form a heterocycloalkyl group , which is optionally substitutedwith one or more of keto or thioketo.
 35. The compound, prodrug,pharmaceutically acceptable salt, pharmaceutically active metabolite, orpharmaceutically acceptable solvate according to claim 16, wherein Z andZ¹ are each independently selected from H, lower alkyl which isunsubstituted or substituted with one or more suitable substituents,—CO₂H, —CO₂-alkyl and —CO₂-cycloalkyl, or taken together with the atomto which they are attached form a heterocycloalkyl group, which isoptionally substituted with one or more of keto or thioketo.
 36. Thecompound, prodrug, pharmaceutically acceptable salt, pharmaceuticallyactive metabolite, or pharmaceutically acceptable solvate according toclaim 20, wherein Z and Z¹ are each independently selected from H, loweralkyl which is unsubstituted or substituted with one or more suitablesubstituents, —CO₂H, —CO₂-alkyl and —CO₂-cycloalkyl, or taken togetherwith the atom to which they are attached form a heterocycloalkyl group,which is optionally substituted with one or more of keto or thioketo.37. The compound, prodrug, pharmaceutically acceptable salt,pharmaceutically active metabolite, or pharmaceutically acceptablesolvate according to any one of claims 8, 12, 13 or 19, wherein Z and Z¹are not both H.
 38. The compound according to claim 9, wherein Z¹ is Hand Z is —CO₂CH₂CH₃, —CO₂(CH(CH₃)₂), —CO₂(C(CH₃)₃), —CO₂CH₂(C(CH₃)₃),—CO₂(cyclo-C₅H₉) or Z¹ and Z taken together with the atom to which theyare attached form


39. The compound according to claim 16, wherein Z¹ is H and Z is—CO₂CH₂CH₃, —CO₂(CH(CH₃)₂), —CO₂(C(CH₃)₃), —CO₂CH₂(C(CH₃)₃),—CO₂(cyclo-C₅H₉) or Z¹ and Z taken together with the atom to which theyare attached form


40. The compound, prodrug, pharmaceutically acceptable salt,pharmaceutically active metabolite, or pharmaceutically acceptablesolvate according to any one of claims 1, 8, 12, 13 or 19, wherein Z¹ isH or a lower alkyl and Z is —CO₂H, —CO₂-alkyl, —CO₂-alkylaryl,—CO₂-alkylheteroaryl, —CO₂-cycloalkyl group, where the lower alkyl,-alkyl, -cycloalkyl, -alkylaryl, -alkylheteroaryl moieties thereof areunsubstituted or substituted with one or more suitable substituents, orZ¹ and Z taken together with the atom to which they are attached form aheterocycloalkyl group, which is optionally substituted.
 41. Thecompound, prodrug, pharmaceutically acceptable salt, pharmaceuticallyactive metabolite, or pharmaceutically acceptable solvate according oneof claims 8, 12, 13, 19 or 20, wherein Z is selected fromethoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl,(2,2-dimethylpropyl)-oxycarbonyl, benzyloxycarbonyl,pyridylmethyleneoxycarbonyl, cyclobutyloxycarbonyl,cyclopentyloxycarbonyl, cyclohexyloxycarbonyl andcycloheptyloxycarbonyl, where the ethoxy, t-butoxy, isopropoxy,(2,2-dimethylpropyl)-oxy, benzyl, pyridylmethylene, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl moieties thereof areunsubstituted or substituted with one or more suitable substituents, orZ¹ and Z taken together with the atom to which they are attached form


42. The compound, prodrug, pharmaceutically acceptable salt,pharmaceutically active metabolite, or pharmaceutically acceptablesolvate according claim 41, wherein Z is selected from ethoxycarbonyl,t-butoxycarbonyl, isopropoxycarbonyl, (2,2-dimethylpropyl)-oxycarbonyl,benzyloxycarbonyl, pyridylmethyleneoxycarbonyl, cyclobutyloxycarbonyl,cyclopentyloxycarbonyl, cyclohexyloxycarbonyl andcycloheptyloxycarbonyl, or Z¹ and Z taken together with the atom towhich they are attached form


43. The compound according to claim 10, having the formula:

wherein R^(a′) is an alkyl, cycloalkyl, aryl or heteroaryl group, wheresaid alkyl, cycloalkyl, aryl, and heteroaryl group is unsubstituted orsubstituted with one or more suitable substituents, and each R⁴, R⁵, R⁶,R⁷, Z and Z¹ are defined as in claim
 10. 44. The compound according toclaim 11, having the formula:

wherein R^(a′) is an alkyl, cycloalkyl, aryl or heteroaryl group, wheresaid alkyl, cycloalkyl, aryl, and heteroaryl group is unsubstituted orsubstituted with one or more suitable substituents, and each R⁴, R⁵, R⁶,R⁷, Z and Z¹ are defined as in claim
 11. 45. The compound according toclaim 12, having the formula:

wherein R¹ is an alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroarylgroup, where the alkyl, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl group is unsubstituted or substituted with one or moresuitable substituents, and each R¹, R², R³, R⁴, R⁵, R⁶, R⁷, Z and Z¹ aredefined as in claim
 12. 46. The compound according to claim 13, havingthe formula:

wherein R¹, R², R⁴, R⁵, R⁶, R⁷, Z and Z¹ are defined as in claim
 13. 47.The compound according to claim 14, having the formula:

wherein R^(z), R³, R⁴, R⁶, R⁷, Z and Z¹ are defined as in claim
 14. 48.The compound according to claims 12 or 13, wherein R¹ is selected from Hand a lower alkyl, phenyl, naphthyl, pyridyl, quinoyl, isoquinoyl orisoxazoyl group, where the lower alkyl, phenyl, naphthyl, pyridyl,quinoyl, isoquinoyl or isoxazoyl group is unsubstituted or substitutedwith one or more substituents selected from alkyl, hydroxy, halo,haloalkyl, alkoxy, halo alkoxy and alkylenedioxy moiety.
 49. Anantipicornaviral compound having the formula:

wherein: R^(a) is (C₁-C₄)alkylcarbonyl-(C₁-C₄)alkyl,(C₃-C₈)cycloalkylcarbonyl-(C₁-C₄)alkyl, arylcarbonyl-(C₁-C₄)alkyl,heteroarylcarbonyl-(C₁-C₄)alkyl, (C₁-C₄)alkylcarbonylamino-(C₁-C₄)alkyl,(C₃-C₈) cycloalkylcarbonylamino-(C₁-C₄)alkyl,heterocycloalkylcarbonylamino-(C₁-C₄)alkyl,arylcarbonylamino-(C₁-C₄)alkyl, heteroarylcarbonylamino-(C₁-C₄)alkyl,(C₁-C₄ alkylaminocarbonyl-(C₁-C₄)alkyl,(C₃-C₈)cycloalkylaminocarbonyl-(C₁-C₄)alkyl,heterocycloalkylaminocarbonyl-(C₁-C₄)alkyl,arylaminocarbonyl-(C₁-C₄)alkyl, heteroarylaminocarbonyl-(C₁-C₄)alkyl,wherein each (C₁-C₄)alkyl, (C₃-C₈)cycloalkyl, heterocycloalkyl, aryl andheteroaryl moiety thereof is unsubstituted or substituted with one ormore suitable substituents; R^(b) and R^(d) are each independently H orC₁-C₄ alkyl; R^(c) is selected from —CH₂CH₂C(O)NH₂; —CH₂CH₂C(O)NH-alkyl;—CH₂NHC(O)CH₃; and

where n is 1 or 2; and Z¹ is H or C₁-C₄ alkyl and Z is —CO₂-alkyl,—CO₂-cycloalkyl, —CO₂-alkylaryl or —CO₂-alkylheterocycloaryl, or Z¹ andZ taken together with the atom to which they are attached form

provided that R^(c) is

where n is 1 or 2 when R^(a) is an indolylcarbonylamino-(C₁-C₄)alkylgroup where the indolyl moiety thereof is substituted with one or moresuitable substituents or R^(a) is is not an amino-substituted(C₁-C₄)alkylcarbonylamino-(C₁-C₄)alkyl or R^(a) is is not anamino-substituted (C₁-C₄)alkylcarbonyl-(C₁-C₄)alkyl; and R^(c) isselected from —CH₂CH₂C(O)NH₂; —CH₂CH₂C(O)NH-alkyl; —CH₂NHC(O)CH₃; and

where n is 1 or 2, when R^(a) is an indolylcarbonylamino-(C₁-C₄)alkylgroup where the indolyl moiety thereof is unsubstituted or R^(a) is a(C₁-C₄) alkylaminocarbonyl-(C₁-C₄)alkyl,(C₃-C₈)cycloalkylaminocarbonyl-(C₁-C₄)alkyl,heterocycloalkylaminocarbonyl-(C₁-C₄)alkyl,arylaminocarbonyl-(C₁-C₄)alkyl, heteroarylaminocarbonyl-(C₁-C₄)alkyl, orheteroarylcarbonylamino-(C₁-C₄)alkyl group, wherein each (C₁-C₄)alkyl,(C₃-C₈)cycloalkyl, heterocycloalkyl, aryl and heteroaryl moiety thereofis unsubstituted or substituted with one or more suitable substituents.50. The compound according to claim 49, wherein: R^(a) is(C₁-C₄)alkylcarbonyl-(C₁-C₄)alkyl,(C₅-C₆)cycloalkylcarbonyl-(C₁-C₄)alkyl, arylcarbonyl-(C₁-C₄)alkyl,heteroarylcarbonyl-(C₁-C₄)alkyl, (C₁-C₄)alkylcarbonylamino-(C₁-C₄)alkyl,C₃-C₈ cycloalkylcarbonylamino-(C₁-C₄)alkyl,heterocycloalkylcarbonylamino-(C₁-C₄)alkyl,arylcarbonylamino-(C₁-C₄)alkyl, heteroarylcarbonylamino-(C₁-C₄)alkyl,(C₁-C₄ alkylaminocarbonyl-(C₁-C₄)alkyl,(C₅-C₆)cycloalkylaminocarbonyl-(C₁-C₄)alkyl,heterocycloalkylaminocarbonyl-(C₁-C₄)alkyl,arylaminocarbonyl-(C₁-C₄)alkyl, heteroarylaminocarbonyl-(C₁-C₄)alkyl,wherein each (C₁-C₄)alkyl, (C₃-C₈)cycloalkyl, heterocycloalkyl, aryl andheteroaryl moiety thereof is unsubstituted or substituted with one ormore suitable substituents; R^(c) is —CH₂CH₂C(O)NH₂ or

where n is 1; and Z¹ is H and Z is —CO₂CH₂CH₃, —CO₂(CH(CH₃)₂),—CO₂(C(CH₃)₃), —CO₂CH₂(C(CH₃)₃), —CO₂(cyclo-C₅H₉) or Z¹ and Z takentogether with the atom to which they are attached form

R^(c) is

where n is 1, when R^(a) is an indolylcarbonylamino-(C₁-C₄)alkyl groupwhere the indolyl moiety thereof is substituted with one or twosubstituents independently selected from halo, C₁-C₄ alkoxy,unsubstituted C₁-C₄ alkyl and C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy,methylenedioxy, aryl, heterocycloalkyl, and heteroaryl where the aryl,heterocycloalkyl and heteroaryl is unsubstituted or substituted by oneore more substituents independently selected from halo, C₁-C₄ alkyl,C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy and methylenedioxy; andR^(c) is selected from —CH₂CH₂C(O)NH₂; —CH₂CH₂C(O)NH-alkyl;—CH₂NHC(O)CH₃; and

where n is 1, when R^(a) is (C₁-C₄)alkylcarbonyl-(C₁-C₄)alkyl,(C₅-C₆)cycloalkyl carbonyl-(C₁-C₄)alkyl, arylcarbonyl-(C₁-C₄)alkyl,heteroarylcarbonyl-(C₁-C₄)alkyl, (C₁-C₄)alkylcarbonylamino-(C₁-C₄)alkyl,C₃-C₈ cycloalkylcarbonylamino-(C₁-C₄)alkyl,heterocycloalkylcarbonylamino-(C₁-C₄)alkyl,arylcarbonylamino-(C₁-C₄)alkyl, heteroarylcarbonylamino-(C₁-C₄)alkyl,(C₁-C₄ alkylaminocarbonyl-(C₁-C₄)alkyl,(C₃-C₈)cycloalkylaminocarbonyl-(C₁-C₄)alkyl,heterocycloalkylaminocarbonyl-(C₁-C₄)alkyl,arylaminocarbonyl-(C₁-C₄)alkyl, heteroarylaminocarbonyl-(C₁-C₄)alkyl,wherein each (C₁-C₄)alkyl, (C₃-C₈)cycloalkyl, heterocycloalkyl, aryl andheteroaryl moiety thereof unsubstituted or substituted with one or moresuitable substituents.
 51. The compound according to claim 49, wherein:R^(a) is (C₁-C₄)alkylcarbonyl-(C₁-C₄)alkyl, phenylcarbonyl-(C₁-C₄)alkyl,naphthylcarbonyl-(C₁-C₄)alkyl, pyrrolylcarbonyl-(C₁-C₄)alkyl,indolylcarbonyl-(C₁-C₄)alkyl, (C₁-C₄)alkylcarbonylamino-(C₁-C₄)alkyl,pyrrolylcarbonylamino-(C₁-C₄)alkyl, indolylcarbonylamino-(C₁-C₄)alkyl,phenylcarbonylamino-(C₁-C₄)alkyl, naphthylcarbonylamino-(C₁-C₄)alkyl,(C₁-C₄)alkylaminocarbonyl-(C₁-C₄)alkyl,phenylaminocarbonyl-(C₁-C₄)alkyl, naphthylaminocarbonyl-(C₁-C₄)alkyl,wherein each (C₁-C₄)alkyl, phenyl, naphthyl, pyrrolyl, and indolylmoiety thereof is unsubstituted or substituted with one or moresubstituents independently selected from halo, C₁-C₄ alkyl, C₁-C₄haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, methylenedioxy, aryl,heterocycloalkyl, and heteroaryl, where the aryl, heterocycloalkyl orheteroaryl is unsubstituted or substituted by one ore more substituentsindependently selected from halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, C₁-C₄ haloalkoxy and methylenedioxy; R^(b) and R^(d) are each H;R^(c) is —CH₂CH₂C(O)NH₂ or

and Z¹ is H and Z is —CO₂CH₂CH₃ or Z¹ and Z taken together with the atomto which they are attached form

provided that R^(c) is

when R^(a) is an indolylcarbonylamino-(C₁-C₄)alkyl group where theindolyl moiety thereof is substituted with one or two substituentsindependently selected from halo, C₁-C₄ alkoxy, unsubstituted C₁-C₄alkyl and C₁-C₄ haloalkyl; and and R^(c) is —CH₂CH₂C(O)NH₂ or

when R^(a) is (C₁-C₄)alkylcarbonyl-(C₁-C₄)alkyl,phenylcarbonyl-(C₁-C₄)alkyl, naphthylcarbonyl-(C₁-C₄)alkyl,pyrrolylcarbonyl-(C₁-C₄)alkyl, indolylcarbonyl-(C₁-C₄)alkyl,(C₁-C₄)alkylcarbonylamino-(C₁-C₄)alkyl,pyrrolylcarbonylamino-(C₁-C₄)alkyl, indolylcarbonylamino-(C₁-C₄)alkyl,phenylcarbonylamino-(C₁-C₄)alkyl, naphthylcarbonylamino-(C₁-C₄)alkyl,(C₁-C₄)alkylaminocarbonyl-(C₁-C₄)alkyl,phenylaminocarbonyl-(C₁-C₄)alkyl, naphthylaminocarbonyl-(C₁-C₄)alkyl,wherein each (C₁-C₄)alkyl, phenyl, naphthyl and pyrrolyl moiety thereofis group is unsubstituted or substituted with one or more substituentsindependently selected from halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, C₁-C₄ haloalkoxy, methylenedioxy, aryl, heterocycloalkyl, andheteroaryl, where the aryl, heterocycloalkyl and heteroaryl isunsubstituted or substituted by one ore more substituents independentlyselected from halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄haloalkoxy and methylenedioxy; and said indolyl moiety is unsubstituted.52. The compound according to claim 49 having the formula:

wherein: R^(a′) is a (C₁-C₄)alkyl, (C₃-C₈)cycloalkyl, aryl or heteroarylgroup, wherein the (C₁-C₄)alkyl, (C₃-C₈)cycloalkyl, aryl and heteroarylgroup is unsubstituted or substituted with one or more substituentsindependently selected from (C₁-C₄)alkyl, aryl, (C₃-C₈)cycloalkyl,heterocycloalkyl, heteroaryl, halo, hydroxyl, (C₁-C₄)alkoxy,alkylenedioxy, aryloxy, (C₃-C₈)cycloalkoxy, heteroaryloxy, and carboxylwhere the (C₁-C₄)alkyl, aryl, (C₃-C₈)cycloalkyl, heterocycloalkyl,heteroaryl moieties thereof are optionally substituted by one or more of(C₁-C₄)alkyl, (C₁-C₄)haloalkyl or aryl, where the aryl is unsubstitutedor substituted with one or more substituents independently selected fromalkyl, haloalkyl, alkylenedioxy, nitro, amino, hydroxamino, alkylamino,dialkylamino, halo, hydroxyl, alkoxy, haloalkoxy, aryloxy, mercapto,alkylthio or arylthio; R^(b) and R^(d) are each independently H or C₁-C₄alkyl; n is 1, 2 or 3; R^(x) is H and R^(y) is H, C₁-C₄ alkyl, C₁-C₄haloalkyl or an arylalkyl, heteroarylalkyl, cycloalkylalkyl group or astraight-chain saturated hydrocarbon moiety or an unsaturatedhydrocarbon moiety, where the arylalkyl, heteroarylalkyl,cycloalkylalkyl group is unsubstituted or substituted with one or moresuitable substituents; R^(c) is

where n is 1 or 2; and Z¹ is H or C₁-C₄ alkyl and Z is —CO₂-alkyl,—CO₂-cycloalkyl, —CO₂-alkylaryl or —CO₂-alkylheterocycloaryl, or Z¹ andZ taken together with the atom to which they are attached form


53. The compound according to claim 52, wherein: R^(a′) is a(C₁-C₄)alkyl, pyrrolyl, indolyl, phenyl or naphthyl group, where the(C₁-C₄)alkyl group is unsubstituted or substituted with one or moresubstituents independently selected from halo, C₁-C₄ alkoxy or C₁-C₄haloalkoxy and the pyrrolyl, indolyl, phenyl or naphthyl group isunsubstituted or substituted with one or more substituents independentlyselected from halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄haloalkoxy, methylenedioxy, aryl, heterocycloalkyl and heteroaryl, wherethe aryl, heterocycloalkyl and heteroaryl is unsubstituted orsubstituted by one or more substituents independently selected fromhalo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy andmethylenedioxy R^(b) and R^(d) are each H; n is 1 or 2; R^(x) is H andR^(y) is substituted or unsubstituted methyl, ethyl, n-propyl,iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl,2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, -methylthienylor benzyl, where the substituted methyl, ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl,2-propyn-1-yl, 3-methyl-3-buten-1-yl, and -methylcyclohexyl issubstituted by one or more substituents independently selected fromhalo, alkoxy, aryloxy, alkylthio and arylthio; the subsituted thienyl issubstituted by one or more substituents independently selected fromlower alkyl, lower alkoxy, hydroxy, amino, alkylamino, dialkylamino andhalo; and the phenyl moiety of the substituted benzyl is substituted byone or more substituents independently selected from lower alkyl, loweralkoxy, alkylenedioxy, hydroxy, amino, alkylamino, dialkylamino andhalo; R^(c) is

where n is 1; and Z¹ is H and Z is —CO₂CH₂CH₃, —CO₂(CH(CH₃)₂),—CO₂(C(CH₃)₃), —CO₂CH₂(C(CH₃)₃), —CO₂(cyclo-C₅H₉) or Z¹ and Z takentogether with the atom to which they are attached form


54. The compound according to claim 52, wherein: R^(a′) is anunsubstituted (C₁-C₄)alkyl, or a pyrrolyl, indolyl, phenyl or naphthylgroup, where the pyrrolyl, indolyl, phenyl or naphthyl group isunsubstituted or substituted by one or more substituents independentlyselected from halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl or a phenyl, naphthyl,isoxazolyl, pyridyl, quinoyl or isoquinoyl group, where the phenyl,naphthyl, isoxazolyl, pyridyl, quinoyl or isoquinoyl group isunsubstituted or substituted with one or more substituents independentlyselected from halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄haloalkoxy and methylenedioxy; R^(b) and R^(d) are each H; n is 2; R^(x)is H and R^(y) is ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl,iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl,3-methyl-3-buten-1-yl, -methylcyclohexyl, benzyl or substituted benzyl,wherein the phenyl moiety of the substituted benzyl comprises one ormore substituents independently selected from C₁-C₄ alkyl, C₁-C₄ alkoxyand halo; R^(c) is

and Z¹ is H and Z is —CO₂CH₂CH₃ or Z¹ and Z taken together with the atomto which they are attached form


55. The compound according to claim 49, having the formula:

wherein: R^(a′) is a (C₁-C₄)alkyl, phenyl, naphthyl, pyrrolyl or indolylgroup, where the (C₁-C₄)alkyl group is unsubstituted or substituted withone or more substituents independently selected from halo, C₁-C₄ alkoxyor C₁-C₄ haloalkoxy and the phenyl, naphthyl, pyrrolyl or indolyl groupis unsubstituted or substituted with one or more substituentsindependently selected from halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, C₁-C₄ haloalkoxy, methylenedioxy, aryl, heterocycloalkyl, andheteroaryl, where the aryl, heterocycloalkyl or heteroaryl isunsubstituted or substituted by one ore more substituents independentlyselected from halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄haloalkoxy and methylenedioxy; n is 1, 2 or 3, R^(x) is H and R^(y) isH, C₁-C₄ alkyl, C₁-C₄ haloalkyl or an arylalkyl, heteroarylalkyl,cycloalkylalkyl group or a straight-chain saturated hydrocarbon moietyor an unsaturated hydrocarbon moiety, where the arylalkyl,heteroarylalkyl, cycloalkylalkyl group is unsubstituted or substitutedwith one or more suitable substituents. R^(b) and R^(d) are eachindependently H or C₁-C₄ alkyl; R^(c) is

where n is 1 or 2; and Z¹ is H or C₁-C₄ alkyl and Z is —CO₂-alkyl,—CO₂-cycloalkyl, —CO₂-alkylaryl or —CO₂-alkylheterocycloaryl, or Z¹ andZ taken together with the atom to which they are attached form


56. The compound according to claim 55, wherein: R^(a′) is a pyrrolyl orindolyl group, where the pyrrolyl or indolyl group is unsubstituted orsubstituted by one or more substituents independently selected fromhalo, C₁-C₄ alkyl, C₁-C₄ haloalkyl or a phenyl, naphthyl, isoxazolyl,pyridyl, quinoyl or isoquinoyl group, where the phenyl, naphthyl,isoxazolyl, pyridyl, quinoyl or isoquinoyl group is unsubstituted orsubstituted with one or more substituents independently selected from:halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy andmethylenedioxy; R^(b) and R^(d) are each H; n is 1 or 2; R^(x) is H andR^(y) is substituted or unsubstituted methyl, ethyl, n-propyl,iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl,2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, -methylthienylor benzyl, where the substituted methyl, ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl,2-propyn-1-yl, 3-methyl-3-buten-1-yl, and -methylcyclohexyl issubstituted by one or more substituents independently selected fromhalo, alkoxy, aryloxy, alkylthio and arylthio; the subsituted thienyl issubstituted by one or more substituents independently selected fromlower alkyl, lower alkoxy, hydroxy, amino, alkylamino, dialkylamino andhalo; and the phenyl moiety of the substituted benzyl is substituted byone or more substituents independently selected from lower alkyl, loweralkoxy, alkylenedioxy, hydroxy, amino, alkylamino, dialkylamino andhalo; R^(c) is

where n is 1; and Z¹ is H and Z is —CO₂CH₂CH₃, —CO₂(CH(CH₃)₂),—CO₂(C(CH₃)₃), —CO₂CH₂(C(CH₃)₃), —CO₂(cyclo-C₅H₉) or Z¹ and Z takentogether with the atom to which they are attached form


57. The compound according to claim 55, wherein: R^(a′) is a pyrrolylgroup that is unsubstituted or substituted by phenyl, α-naphthyl,β-naphthyl, 2-chlorophenyl, 2-α,α,α-trifluoromethylphenyl,3-chloro-6-methoxyphenyl, 2,3-dichlorophenyl, 4-isoquinoyl,3-iso-propylphenyl, 2,5-dimethoxyphenyl, 2-methoxyphenyl, 2-methylphenyl(o-tolyl), 2-bromophenyl, 3-pyridyl, 4-pyridyl, 3-methyl-isoxazol-5-yl,3,3,3-trifluoroprop-1-yl, or 2,3-benzo[d]dioxolyl; R^(b) and R^(d) areeach H; n is 1; R^(x) is H and R^(y) is ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl,2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, benzyl orsubstituted benzyl, wherein the phenyl moiety of the substituted benzylcomprises one or more substituents independently selected from C₁-C₄alkyl, C₁-C₄ alkoxy and halo; R^(c) is

and Z¹ is H and Z is —CO₂CH₂CH₃ or Z¹ and Z taken together with the atomto which they are attached form


58. The compound according to claim 49, having the formula:

wherein: R^(a′) is a (C₁-C₄)alkyl, (C₃-C₈)cycloalkyl, heterocycloalkyl,aryl or heteroaryl group, wherein the (C₁-C₄)alkyl, (C₃-C₈)cycloalkyl,heterocycloalkyl, aryl and heteroaryl group is unsubstituted orsubstituted with one or more suitable substituents; n is 1, 2 or 3;R^(x) is H and R^(y) is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl or an arylalkyl,heteroarylalkyl, cycloalkylalkyl group or a straight-chain saturatedhydrocarbon moiety or an unsaturated hydrocarbon moiety, where thearylalkyl, heteroarylalkyl, cycloalkylalkyl group is unsubstituted orsubstituted with one or more suitable substituents; R^(c) is selectedfrom —CH₂CH₂C(O)NH₂; —CH₂CH₂C(O)NH-alkyl; —CH₂NHC(O)CH₃; and

where n is 1 or 2; and Z¹ is H or C₁-C₄ alkyl and Z is —CO₂-alkyl,—CO₂-cycloalkyl, —CO₂-alkylaryl or —CO₂-alkylheterocycloaryl, or Z¹ andZ taken together with the atom to which they are attached form


59. The compound according to claim 58, wherein: R^(a′) is a(C₁-C₄)alkyl, phenyl or naphthyl group, where the (C₁-C₄)alkyl group isunsubstituted or substituted with one or more substituents independentlyselected from halo, C₁-C₄ alkoxy or C₁-C₄ haloalkoxy and the phenyl ornaphthyl group is unsubstituted or substituted with one or moresubstituents independently selected from halo, C₁-C₄ alkyl, C₁-C₄haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, methylenedioxy and phenyl,where the phenyl is unsubstituted or substituted by one or moresubstituents independently selected from halo, C₁-C₄ alkyl, C₁-C₄haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy and methylenedioxy; n is 1 or2; R^(b) and R^(d) are each H; R^(x) is H and R^(y) is H or substitutedor unsubstituted methyl, ethyl, n-propyl, iso-propyl, n-butyl,sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl,3-methyl-3-buten-1-yl, -methylcyclohexyl, -methylthienyl or benzyl,where the substituted methyl, ethyl, n-propyl, iso-propyl, n-butyl,sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl,3-methyl-3-buten-1-yl, and -methylcyclohexyl is substituted by one ormore substituents independently selected from halo, alkoxy, aryloxy,alkylthio and arylthio; the subsituted thienyl is substituted by one ormore substituents independently selected from lower alkyl, lower alkoxy,hydroxy, amino, alkylamino, dialkylamino and halo; and the phenyl moietyof the substituted benzyl is substituted by one or more substituentsindependently selected from lower alkyl, lower alkoxy, alkylenedioxy,hydroxy, amino, alkylamino, dialkylamino and halo; R^(c) is—CH₂CH₂C(O)NH₂ or

where n is 1; and Z¹ is H and Z is —CO₂CH₂CH₃, —CO₂(CH(CH₃)₂),—CO₂(C(CH₃)₃), —CO₂CH₂(C(CH₃)₃), —CO₂(cyclo-C₅H₉) or Z¹ and Z takentogether with the atom to which they are attached form


60. The compound according to claim 58, wherein: R^(a′) is ahalo-substituted phenyl group; n is 2; R^(b) and R^(d) are each H; R^(x)is H and R^(y) is H, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl,iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl,3-methyl-3-buten-1-yl, -methylcyclohexyl, benzyl or substituted benzyl,wherein the phenyl moiety of the substituted benzyl comprises one ormore substituents independently selected from C₁-C₄ alkyl, C₁-C₄ alkoxyand halo; R^(c) is —CH₂CH₂C(O)NH₂ or

and Z¹ is H and Z is —CO₂CH₂CH₃ or Z¹ and Z taken together with the atomto which they are attached form


61. The compound according to any one of claims 52-60, wherein R^(y) isH, ethyl, 2-propyn-1-yl, methylcyclohexyl or benzyl.
 62. Anantipicornaviral compound having the formula:

wherein: W is CH or N; R^(a′) is a C₁-C₄ alkyl, C₃-C₈ cycloalkyl, arylor heteroaryl group, where the C₁-C₄ alkyl, C₃-C₈ cycloalkyl, aryl, andheteroaryl group is unsubstituted or substituted with one or moresuitable substituents, provided that R^(a′) is not an amino-substitutedalkyl group; R⁴ and R⁶ are each independently H or C₁-C₄ alkyl; R⁵ is H,C₁-C₄ alkyl, C₁-C₄ haloalkyl or an arylalkyl, heteroarylalkyl,cycloalkylalkyl group or a straight-chain saturated hydrocarbon moietyor an unsaturated hydrocarbon moiety, where the arylalkyl,heteroarylalkyl, cycloalkylalkyl group is unsubstituted or substitutedwith one or more suitable substituents; R⁷ is

where n is 1 or 2; and Z¹ is H or C₁-C₄ alkyl and Z is —CO₂-alkyl,—CO₂-cycloalkyl, —CO₂-alkylaryl or —CO₂-alkylheterocycloaryl, or Z¹ andZ taken together with the atom to which they are attached form


63. The compound according to claim 62, wherein: R^(a′) is a C₁-C₄alkyl, C₅-C₆ cycloalkyl, phenyl, naphthyl or heteroaryl group, where thephenyl, naphthyl or heteroaryl group is unsubstituted or substitutedwith one or more substituents independently selected from halo, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, methylenedioxy,aryl, heterocycloalkyl, and heteroaryl, where the aryl, heterocycloalkyland heteroaryl is unsubstituted or substituted by one ore moresubstituents independently selected from halo, C₁-C₄ alkyl, C₁-C₄haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy and methylenedioxy; R⁴ and R⁶are each H; R⁵ is H or substituted or unsubstituted methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl,2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl,-methylthienyl or benzyl, where the substituted methyl, ethyl, n-propyl,iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl,2-propyn-1-yl, 3-methyl-3-buten-1-yl, and -methylcyclohexyl issubstituted by one or more substituents independently selected fromhalo, alkoxy, aryloxy, alkylthio and arylthio; the subsituted thienyl issubstituted by one or more substituents independently selected fromlower alkyl, lower alkoxy, hydroxy, amino, alkylamino, dialkylamino andhalo; and the phenyl moiety of the substituted benzyl is substituted byone or more substituents independently selected from lower alkyl, loweralkoxy, alkylenedioxy, hydroxy, amino, alkylamino, dialkylamino andhalo; R⁷ is

where n is 1; and Z¹ is H and Z is —CO₂CH₂CH₃, —CO₂(CH(CH₃)₂),—CO₂(C(CH₃)₃), —CO₂CH₂(C(CH₃)₃), —CO₂(cyclo-C₅H₉) or Z¹ and Z takentogether with the atom to which they are attached form


64. The compound according to claim 62, wherein: R^(a′) is a C₁-C₄alkyl, C₁-C₆ cycloalkyl, phenyl, naphthyl, pyrrolyl or indolyl, group,where the phenyl, naphthyl, pyrrolyl or indolyl, group is unsubstitutedor substituted with one or more substituents independently selected fromhalo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy,methylenedioxy and a phenyl, naphthyl, isoquinoyl, pyridyl or isoxazolylgroup, wherein the phenyl, naphthyl, isoquinoyl, pyridyl and isoxazolylgroup is unsubstituted or substituted by one ore more substituentsindependently selected from halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, C₁-C₄ haloalkoxy and methylenedioxy; R⁴ and R⁶ are each H; R⁵ isH, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl,-methylcyclohexyl, benzyl or substituted benzyl, wherein the phenylmoiety of the substituted benzyl comprises one or more substituentsindependently selected from C₁-C₄ alkyl, C₁-C₄ alkoxy and halo; R⁷ is

and Z¹ is H and Z is —CO₂CH₂CH₃ or Z¹ and Z taken together with the atomto which they are attached form


65. The compound according to claim 62, having the formula:


66. The compound according to claim 62, having the formula:


67. An antipicornaviral compound having the formula:

wherein: R¹ is H, halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or an aryl orheteroaryl group, where the aryl or heteroaryl group is unsubstituted orsubstituted with one or more suitable substituents; R² and R³ are eachindependently H or C₁-C₄ alkyl; or or R¹ together with R² form acycloalkyl, heterocycloalkyl, aryl or heteroaryl ring, where thecycloalkyl, heterocycloalkyl, aryl or heteroaryl ring is unsubstitutedor substituted with one or more suitable substituents; R⁴ and R⁶ areeach independently H or C₁-C₄ alkyl; R⁵ is H, C₁-C₄ alkyl, C₁-C₄haloalkyl or an arylalkyl, heteroarylalkyl, cycloalkylalkyl group or astraight-chain saturated hydrocarbon moiety or an unsaturatedhydrocarbon moiety, where the arylalkyl, heteroarylalkyl,cycloalkylalkyl group is unsubstituted or substituted with one or moresuitable substituents; R⁷ is selected from —CH₂CH₂C(O)NH₂;—CH₂CH₂C(O)NH-alkyl; —CH₂NHC(O)CH₃; and

where n is 1 or 2; and Z¹ is H or C₁-C₄ alkyl and Z is —CO₂-alkyl,—CO₂-cycloalkyl, —CO₂-alkylaryl or —CO₂-alkylheterocycloaryl, or Z¹ andZ taken together with the atom to which they are attached form


68. The compound according to claim 67, wherein: R¹ is H, halo, C₁-C₄alkyl, C₁-C₄ haloalkyl or a phenyl, naphthyl, isoxazolyl, pyridyl,quinoyl or isoquinoyl group, where the phenyl, naphthyl, isoxazolyl,pyridyl, quinoyl or isoquinoyl group is unsubstituted or substitutedwith one or more substituents independently selected from: halo, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy andmethylenedioxy; R² and R³ are each H; or R¹ together with R² form aphenyl ring, which is unsubstituted or substituted with one or moresuitable substituents and R³ is H; R⁴ and R⁶ are each H; R⁵ is H orsubstituted or unsubstituted methyl, ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl,2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, -methylthienylor benzyl, where the substituted methyl, ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl,2-propyn-1-yl, 3-methyl-3-buten-1-yl, and -methylcyclohexyl issubstituted by one or more substituents independently selected fromhalo, alkoxy, aryloxy, alkylthio and arylthio; the subsituted thienyl issubstituted by one or more substituents independently selected fromlower alkyl, lower alkoxy, hydroxy, amino, alkylamino, dialkylamino andhalo; and the phenyl moiety of the substituted benzyl is substituted byone or more substituents independently selected from lower alkyl, loweralkoxy, alkylenedioxy, hydroxy, amino, alkylamino, dialkylamino andhalo; R⁷ is —CH₂CH₂C(O)NH₂ or

where n is 1; and Z¹ is H and Z is —CO₂CH₂CH₃, —CO₂(CH(CH₃)₂),—CO₂(C(CH₃)₃), —CO₂CH₂(C(CH₃)₃), —CO₂(cyclo-C₅H₉) or Z¹ and Z takentogether with the atom to which they are attached form


69. The compound according to claim 67, wherein: R¹ is H, phenyl,α-naphthyl, β-naphthyl, 2-chlorophenyl, 2-α,α,α-trifluoromethylphenyl,3-chloro-6-methoxyphenyl, 2,3-dichlorophenyl, 4-isoquinoyl,3-iso-propylphenyl, 2,5-dimethoxyphenyl, 2-methoxyphenyl,2-methylphenyl, 2-bromophenyl, 3-pyridyl, 4-pyridyl,3-methyl-isoxazol-5-yl, 3,3,3-trifluoroprop-1-yl, or2,3-benzo[d]dioxolyl; R² and R³ are each H; R⁴ and R⁶ are each H; R⁵ isH, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl,-methylcyclohexyl, benzyl or substituted benzyl, wherein the phenylmoiety of the substituted benzyl comprises one or more substituentsindependently selected from C₁-C₄ alkyl, C₁-C₄ alkoxy and halo; R⁷ is—CH₂CH₂C(O)NH₂ or

and Z¹ is H and Z is —CO₂CH₂CH₃ or Z¹ and Z taken together with the atomto which they are attached form


70. An antipicornaviral compound having the formula:

wherein: R¹ is H, halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or an aryl orheteroaryl group, where the aryl or heteroaryl group is unsubstituted orsubstituted with one or more suitable substituents; R² and R³ are eachindependently H or C₁-C₄ alkyl; or or R¹ together with R² form acycloalkyl, heterocycloalkyl, aryl or heteroaryl ring, where thecycloalkyl, heterocycloalkyl, aryl or heteroaryl ring is unsubstitutedor substituted with one or more suitable substituents; R⁴ and R⁶ areeach independently H or C₁-C₄ alkyl; R⁵ is H, C₁-C₄ alkyl, C₁-C₄haloalkyl or an arylalkyl, heteroarylalkyl, cycloalkylalkyl group or astraight-chain saturated hydrocarbon moiety or an unsaturatedhydrocarbon moiety, where the arylalkyl, heteroarylalkyl,cycloalkylalkyl group is unsubstituted or substituted with one or moresuitable substituents; R⁷ is selected from —CH₂CH₂C(O)NH₂;—CH₂CH₂C(O)NH-alkyl; —CH₂NHC(O)CH₃; and

where n is 1 or 2; and Z¹ is H or C₁-C₄ alkyl and Z is —CO₂-alkyl,—CO₂-cycloalkyl, —CO₂-alkylaryl or —CO₂-alkylheterocycloaryl, or Z¹ andZ taken together with the atom to which they are attached form

provided that when R¹ together with R² form a phenyl ring and the phenylring is substituted, R⁷ is

where n is 1 or
 2. 71. The compound according to claim 70, wherein: R¹is H, halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl or a phenyl, naphthyl,isoxazolyl, pyridyl, quinoyl or isoquinoyl group, where the phenyl,naphthyl, isoxazolyl, pyridyl, quinoyl or isoquinoyl group isunsubstituted or substituted with one or more substituents independentlyselected from halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄haloalkoxy and methylenedioxy; R² and R³ are each H; or R¹ together withR² form an unsubstituted phenyl ring and R³ is H; R⁴ and R⁶ are each H;R⁵ is H or substituted or unsubstituted methyl, ethyl, n-propyl,iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl,2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, -methylthienylor benzyl, where the substituted methyl, ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl,2-propyn-1-yl, 3-methyl-3-buten-1-yl, and -methylcyclohexyl issubstituted by one or more substituents independently selected fromhalo, alkoxy, aryloxy, alkylthio and arylthio; the subsituted thienyl issubstituted by one or more substituents independently selected fromlower alkyl, lower alkoxy, hydroxy, amino, alkylamino, dialkylamino andhalo; and the phenyl moiety of the substituted benzyl is substituted byone or more substituents independently selected from lower alkyl, loweralkoxy, alkylenedioxy, hydroxy, amino, alkylamino, dialkylamino andhalo; R⁷ is —CH₂CH₂C(O)NH₂ or

where n is 1; and Z¹ is H and Z is —CO₂CH₂CH₃, —CO₂(CH(CH₃)₂),—CO₂(C(CH₃)₃), —CO₂CH₂(C(CH₃)₃), —CO₂(cyclo-C₅H₉) or Z¹ and Z takentogether with the atom to which they are attached form


72. The compound according to claim 70, wherein: R¹ is H, phenyl,α-naphthyl, β-naphthyl, 2-chlorophenyl, 2-α,α,α-trifluoromethylphenyl,3-chloro-6-methoxyphenyl, 2,3-dichlorophenyl, 4-isoquinoyl,3-iso-propylphenyl, 2,5-dimethoxyphenyl, 2-methoxyphenyl,2-methylphenyl, 2-bromophenyl, 3-pyridyl, 4-pyridyl,3-methyl-isoxazol-5-yl, 3,3,3-trifluoroprop-1-yl, or2,3-benzo[d]dioxolyl; R² and R³ are each H; R⁴ and R⁶ are each H; R⁵ isH, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl,-methylcyclohexyl, benzyl or substituted benzyl, wherein the phenylmoiety of the substituted benzyl comprises one or more substituentsindependently selected from C₁-C₄ alkyl, C₁-C₄ alkoxy and halo; R⁷ is—CH₂CH₂C(O)NH₂ or

and Z¹ is H and Z is —CO₂CH₂CH₃ or Z¹ and Z taken together with the atomto which they are attached form


73. An antipicornaviral compound having the formula:

wherein: each R^(z) is independently selected from halo and a C₁-C₄alkoxy, C₁-C₄ alkyl, aryl, heterocycloalkyl or heteroaryl group wherethe C₁-C₄ alkoxy or C₁-C₄ alkyl group is unsubstituted or substitutedwith one or more substituents independently selected from halo, C₁-C₄alkoxy or C₁-C₄ haloalkoxy and the aryl, heterocycloalkyl or heteroarylgroup is unsubstituted or substituted by one ore more substituentsindependently selected from halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, C₁-C₄ haloalkoxy and methylenedioxy or two R¹ at adjacentpositions are methylenedioxy; and n_(z) is an integer from 1 to 4; R³ isH, halo, C₁-C₄ alkoxy, unsubstituted C₁-C₄ alkyl, C₁-C₄ haloalkyl andC₁-C₄ alkoxyalkyl; R⁴ and R⁶ are each independently H or C₁-C₄ alkyl; R⁵is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl or an arylalkyl, heteroarylalkyl,cycloalkylalkyl group or a straight-chain saturated hydrocarbon moietyor an unsaturated hydrocarbon moiety, where the arylalkyl,heteroarylalkyl, cycloalkylalkyl group is unsubstituted or substitutedwith one or more suitable substituents; R⁷ is

where n is 1 or 2; and Z¹ is H or C₁-C₄ alkyl and Z is —CO₂-alkyl,—CO₂-cycloalkyl, —CO₂-alkylaryl or —CO₂-alkylheterocycloaryl, or Z¹ andZ taken together with the atom to which they are attached form


74. The compound according to claim 73, wherein each R^(z) isindependently selected from halo, C₁-C₄ alkoxy, unsubstituted C₁-C₄alkyl, C₁-C₄ haloalkyl, and C₁-C₄ alkoxyalkyl and n_(z) is an integerfrom 1 to 2; R³ is H or C₁-C₄ alkyl; R⁴ and R⁶ are each H; R⁵ is H orsubstituted or unsubstituted methyl, ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl,2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, -methylthienylor benzyl, where the substituted methyl, ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl,2-propyn-1-yl, 3-methyl-3-buten-1-yl, and -methylcyclohexyl issubstituted by one or more substituents independently selected fromhalo, alkoxy, aryloxy, alkylthio and arylthio; the subsituted thienyl issubstituted by one or more substituents independently selected fromlower alkyl, lower alkoxy, hydroxy, amino, alkylamino, dialkylamino andhalo; and the phenyl moiety of the substituted benzyl is substituted byone or more substituents independently selected from lower alkyl, loweralkoxy, alkylenedioxy, hydroxy, amino, alkylamino, dialkylamino andhalo; R⁷ is

where n is 1; and Z¹ is H and Z is —CO₂CH₂CH₃, —CO₂(CH(CH₃)₂),—CO₂(C(CH₃)₃), —CO₂CH₂(C(CH₃)₃), —CO₂(cyclo-C₅H₉) or Z¹ and Z takentogether with the atom to which they are attached form


75. The compound according to claim 73, wherein each R^(z) isindependently selected from halo, C₁-C₄ alkoxy, unsubstituted C₁-C₄alkyl and C₁-C₄ haloalkyl, and n_(z) is 1 or 2; R³ is H; R⁴ and R⁶ areeach H; R⁵ is H, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl,iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl,3-methyl-3-buten-1-yl, -methylcyclohexyl, benzyl or substituted benzyl,wherein the phenyl moiety of the substituted benzyl comprises one ormore substituents independently selected from C₁-C₄ alkyl, C₁-C₄ alkoxyand halo; R⁷ is

and Z¹ is H and Z is —CO₂CH₂CH₃ or Z¹ and Z taken together with the atomto which they are attached form


76. An antipicornaviral compound having the formula:

wherein: R^(a′) is a C₁-C₄ alkyl, aryl, C₃-C₇ cycloalkyl,heterocycloalkyl or heteroaryl group, where the C₁-C₄ alkyl, aryl, C₃-C₇cycloalkyl, heterocycloalkyl or heteroaryl group is unsubstituted orsubstituted with one or more substituents independently selected fromalkyl, haloalkyl, alkylenedioxy, nitro, amino, hydroxamino, alkylamino,dialkylamino, halo, hydroxyl, alkoxy, haloalkoxy, aryloxy, mercapto,alkylthio or arylthio, aryl or heteroaryl, where the aryl or heteroarylgroup is unsubstituted or substituted with one or more substituentsindependently selected from halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, C₁-C₄ haloalkoxy and methylenedioxy; each R⁶ is independently Hor C₁-C₄ alkyl; R⁵ is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl or an arylalkyl,heteroarylalkyl, cycloalkylalkyl group or a straight-chain saturatedhydrocarbon moiety or an unsaturated hydrocarbon moiety, where thearylalkyl, heteroarylalkyl, cycloalkylalkyl group is unsubstituted orsubstituted with one or more suitable substituents; R⁷ is selected from—CH₂CH₂C(O)NH₂; —CH₂CH₂C(O)NH-alkyl; —CH₂NHC(O)CH₃; and

where n is 1 or 2; and Z¹ is H or C₁-C₄ alkyl and Z is —CO₂-alkyl,—CO₂-cycloalkyl, —CO₂-alkylaryl or —CO₂-alkylheterocycloaryl, or Z¹ andZ taken together with the atom to which they are attached form


77. The compound according to claim 76, wherein: R^(a′) is a C₁-C₄alkyl, C₁-C₄ haloalkyl, phenyl, naphthyl, C₅-C₆ cycloalkyl, isoquinoyl,pyridyl or pyrrolyl group, where the phenyl, naphthyl, isoquinoyl,pyridyl or pyrrolyl group is unsubstituted or substituted with one ormore substituents independently selected from halo, C₁-C₄ alkyl, C₁-C₄haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy and methylenedioxy; each R⁶ isH; R⁵ is H or substituted or unsubstituted methyl, ethyl, n-propyl,iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl,2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, -methylthienylor benzyl, where the substituted methyl, ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl,2-propyn-1-yl, 3-methyl-3-buten-1-yl, and -methylcyclohexyl issubstituted by one or more substituents independently selected fromhalo, alkoxy, aryloxy, alkylthio and arylthio; the subsituted thienyl issubstituted by one or more substituents independently selected fromlower alkyl, lower alkoxy, hydroxy, amino, alkylamino, dialkylamino andhalo; and the phenyl moiety of the substituted benzyl is substituted byone or more substituents independently selected from lower alkyl, loweralkoxy, alkylenedioxy, hydroxy, amino, alkylamino, dialkylamino andhalo; R⁷ is —CH₂CH₂C(O)NH₂ or

where n is 1; and Z¹ is H and Z is —CO₂CH₂CH₃, —CO₂(CH(CH₃)₂),—CO₂(C(CH₃)₃), —CO₂CH₂(C(CH₃)₃), —CO₂(cyclo-C₅H₉) or Z¹ and Z takentogether with the atom to which they are attached form


78. The compound according to claim 76, wherein: R^(a′) is a phenylgroup, where the phenyl group is unsubstituted or substituted with oneor more substituents independently selected from halo, C₁-C₄ alkyl,C₁-C₄ haloalkyl or C₁-C₄ alkoxy; each R⁶ is H; R⁵ is H, ethyl, n-propyl,iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl,2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, benzyl orsubstituted benzyl, wherein the phenyl moiety of the substituted benzylcomprises one or more substituents independently selected from C₁-C₄alkyl, C₁-C₄ alkoxy and halo; R⁷ is —CH₂CH₂C(O)NH₂ or

; and Z¹ is H and Z is —CO₂CH₂CH₃ or Z¹ and Z taken together with theatom to which they are attached form


79. The compound according to any one of claims 62 to 78, where R⁵ is H,ethyl, 2-propyn-1-yl, methylcyclohexyl or benzyl.
 80. The compoundaccording to any one of claims 1, 8, 9, 12, 13, 14, 19, 20, 49, 62, 67,70, 73 or 76 having antipicornaviral activity corresponding to an EC₅₀less than or equal to 100 μM in an H1-HeLa cell culture assay.
 81. Thecompound according to claim 16, having antipicornaviral activitycorresponding to an EC₅₀ less than or equal to 100 μM in an H1-HeLa cellculture assay.
 82. A pharmaceutical composition comprising: atherapeutically effective amount of at least one antipicornaviral agentselected from compounds, prodrugs, pharmaceutically acceptable salts,pharmaceutically active metabolites, and pharmaceutically acceptablesolvates defined in any one of claims 1, 8, 9, 12, 13, 14, 19, 20, 49,62, 67, 70, 73 or 76; and a pharmaceutically acceptable carrier,diluent, vehicle, or excipient.
 83. The method of treating a mammaliandisease condition mediated by picornaviral protease activity, comprisingadministering to a mammal in need thereof a therapeutically effectiveamount of at least one compound, prodrug, pharmaceutically acceptablesalt, pharmaceutically active metabolite, or pharmaceutically acceptablesolvate defined in any one of claims 1, 8, 9, 12, 13, 14, 19, 20, 49,62, 67, 70, 73 or
 76. 84. The method of inhibiting the activity of apicornaviral 3C protease, comprising contacting the picornaviral 3Cprotease with an effective amount of at least one compound, prodrug,pharmaceutically acceptable salt, pharmaceutically active metabolite, orpharmaceutically acceptable solvate defined in any one of claims 1, 8,9, 12, 13, 14, 19, 20, 49, 62, 67, 70, 73 or
 76. 85. The method asdefined in claim 53, wherein the picornaviral 3C protease is arhinoviral protease.
 86. A compound selected from:


87. The compound according to claim 86, selected from the groupconsisting of: